Acyloxyalkyl carbamate prodrugs of sulfinic acids, methods of synthesis, and use

ABSTRACT

Acyloxyalkyl carbamate prodrugs of 3-aminopropylsulfinic acid and analogs thereof, pharmaceutical compositions of 3-aminopropylsulfinic acid and analogs thereof, methods of making prodrugs of 3-aminopropylsulfinic acid and analogs thereof, methods of using prodrugs of 3-aminopropylsulfinic acid and analogs thereof, and pharmaceutical compositions thereof for treating or preventing diseases or disorders such as spasticity or gastroesophageal reflux disease are disclosed. Acyloxyalkyl carbamate prodrugs of 3-aminopropylsulfinic acid and analogs thereof and sustained release oral dosage forms thereof, which are suitable for oral administration, are also disclosed.

This application claims the benefit under 35 U.S.C. § 119(e) from U.S.Provisional Application Ser. No. 60/625,050 filed Nov. 3, 2004, which isincorporated herein by reference in its entirety.

The disclosure relates to acyloxyalkyl carbamate prodrugs of3-aminopropylsulfinic acid and analogs thereof, pharmaceuticalcompositions comprising 3-aminopropylsulfinic acid and analogs thereof,methods of making prodrugs of 3-aminopropylsulfinic acid and analogsthereof, and methods of using prodrugs of 3-aminopropylsulfinic acid andanalogs thereof, and pharmaceutical compositions thereof to treatvarious diseases or disorders. The disclosure also relates to prodrugsof 3-aminopropylsulfinic acid and analogs thereof suitable for oraladministration, and for oral administration using sustained releasedosage forms.

(±)-4-Amino-3-(4-chlorophenyl)butanoic acid (baclofen), (1),

is an analog of gamma-aminobutyric acid (GABA) that selectivelyactivates GABA_(B) receptors resulting in neuronal hyperpolarization.GABA_(B) receptors are located in laminae I-IV of the spinal cord, whereprimary sensory fibers end. These G-protein coupled receptors activateconductance by K⁺-selective ion channels and can reduce currentsmediated by Ca²⁺ channels in certain neurons. Baclofen has a presynapticinhibitory effect on the release of excitatory neurotransmitters andalso acts postsynaptically to decrease motor neuron firing (see Bowery,Trends Pharmacol. Sci. 1989, 10, 401-407; Misgeld et al., Prog.Neurobiol. 1995, 46, 423-462, each of which is incorporated herein byreference in its entirety).

Many examples of compounds having agonistic or partially agonisticaffinity to GABA_(B) receptors exist and include certain amino acids,aminophosphonic acids, aminophosphinic acids, aminophosphonous acids,and aminosulfinic acids. Examples of 4-aminobutanoic acid GABA_(B)receptor ligands include:

-   4-amino-3-(2-chlorophenyl)butanoic acid;-   4-amino-3-(4-fluorophenyl)butanoic acid;-   4-amino-3-hydroxybutanoic acid;-   4-amino-3-(4-chlorophenyl)-3-hydroxyphenylbutanoic acid;-   4-amino-3-(thien-2-yl)butanoic acid;-   4-amino-3-(5-chlorothien-2-yl)butanoic acid;-   4-amino-3-(5-bromothien-2-yl)butanoic acid;-   4-amino-3-(5-methylthien-2-yl)butanoic acid;-   4-amino-3-(2-imidazolyl)butanoic acid; and-   4-guanidino-3-(4-chlorophenyl)butanoic acid.

Examples of aminopropylphosphonous acid and aminopropylphosphinic analogGABA_(B) receptor ligands include:

-   (3-aminopropyl)phosphonous acid;-   (4-aminobut-2-yl)phosphonous acid;-   (3-amino-2-methylpropyl)phosphonous acid;-   (3-aminobutyl)phosphonous acid;-   (3-amino-2-(4-chlorophenyl)propyl)phosphonous acid;-   (3-amino-2-(4-chlorophenyl)-2-hydroxypropyl)phosphonous acid;-   (3-amino-2-(4-fluorophenyl)propyl)phosphonous acid;-   (3-amino-2-phenylpropyl)phosphonous acid;-   (3-amino-2-hydroxypropyl)phosphonous acid;-   (E)-(3-aminopropen-1-yl)phosphonous acid;-   (3-amino-2-cyclohexylpropyl)phosphonous acid;-   (3-amino-2-benzylpropyl)phosphonous acid;-   [3-amino-2-(4-methylphenyl)propyl]phosphonous acid;-   [3-amino-2-(4-trifluoromethylphenyl)propyl]phosphonous acid;-   [3-amino-2-(4-methoxyphenyl)propyl]phosphonous acid;-   [3-amino-2-(4-chlorophenyl)-2-hydroxypropyl]phosphonous acid;-   (3-aminopropyl)methylphosphinic acid;-   (3-amino-2-hydroxypropyl)methylphosphinic acid;-   (3-aminopropyl)(difluoromethyl)phosphinic acid;-   (4-aminobut-2-yl)methylphosphinic acid;-   (3-amino-1-hydroxypropyl)methylphosphinic acid;-   (3-amino-2-hydroxypropyl)(difluoromethyl)phosphinic acid;-   (E)-(3-aminopropen-1-yl)methylphosphinic acid;-   (3-amino-2-oxo-propyl)methyl phosphinic acid;-   (3-aminopropyl)hydroxymethylphosphinic acid;-   (5-aminopent-3-yl)methylphosphinic acid; and-   (4-amino-1,1,1-trifluorobut-2-yl)methylphosphinic acid.

3-Aminopropylsulfinic acid analog GABA_(B) receptor agonists aredescribed in Carruthers et al., Bioorg. Med. Chem. Lett. 1995, 5,237-240; Shue et al., Bioorg. Med. Chem. Lett. 1996, 6, 1709-1714;Carruthers et al., Bioorg. Med. Chem. Lett. 1998, 8, 3059-3064; andFitzpatrick et al., International Publication No. WO 02/100823, each ofwhich is incorporated herein by reference in its entirety. Examples of3-aminopropylsulfinic acid analog GABA_(B) receptor ligands include:

-   3-aminopropylsulfinic acid;-   (3-amino-2-(4-chlorophenyl)propyl)sulfinic acid;-   (3-amino-2-hydroxypropyl)sulfinic acid;-   (2S)-(3-amino-2-hydroxypropyl)sulfinic acid;-   (2R)-(3-amino-2-hydroxypropyl)sulfinic acid;-   (3-amino-2-fluoropropyl)sulfinic acid;-   (2S)-(3-amino-2-fluoropropyl)sulfinic acid;-   (2R)-(3-amino-2-fluoropropyl)sulfinic acid; and-   (3-amino-2-oxopropyl)sulfinic acid.

A principal pharmacological effect of GABA_(B) receptor agonists inmammals is reduction of muscle tone, and baclofen is frequently used inthe treatment of spasticity. Spasticity is associated with damage to thecorticospinal tract and is a common complication of neurologicaldisease. Diseases and conditions in which spasticity may be a prominentsymptom include cerebral palsy, multiple sclerosis, stroke, head andspinal cord injuries, traumatic brain injury, anoxia, andneurodegenerative diseases. Patients with spasticity complain ofstiffness, involuntary spasm, and pain. These painful spasms may bespontaneous or triggered by a minor sensory stimulus, such as touchingthe patient.

GABA_(B) receptor agonists are also useful in controllinggastroesophageal reflux disease (Lidums et al., Gastroenterology 2000,118, 7-13; Cange et al., Aliment. Pharmacol. Ther. 2002, 16, 869-873;van Herwaarden et al., Aliment. Pharmacol. Ther. 2002, 16, 1655-1662;Zhang et al., Gut 2002, 50, 19-24; Vela et al., Aliment. Pharmacol.Ther. 2003, 17, 243-251; Koek et al., Gut 2003, 52, 1397-1402;Ciccaglione et al., Gut 2003, 52, 464-470; Andrews et al., U.S. Pat. No.6,117,908; Andrews et al., U.S. Pat. No. 6,664,069; Fara et al.,International Publication No. WO 02/096404; and Fitzpatrick et al.,International Publication No. WO 02/100823, each of which isincorporated herein by reference in its entirety). The physiologicprocess by which most reflux episodes occur is transient loweresophageal sphincter relaxation (TLESR). The lower esophageal sphincter(LES) and crural diaphragm each contribute to the sphincteric mechanismthat partitions the stomach from the esophagus and guards againstpathological gastroesophageal reflux (GER) (Mittal et al.,Gastroenterology 1995, 109, 601-610, which is incorporated herein byreference in its entirety). TLESRs are rapid and prolonged relaxationsof the LES and inhibitions of the crural diaphragm that are notinitiated by swallowing. Gastric distension and elevation of serumcholecystokinin (CCK) after eating increases the frequency of TLESRs andthese transient relaxations are important pathophysiologically as theyoccur more frequently in patients with gastroesophageal reflux disease(GERD). TLESRs are believed to account for virtually all reflux episodesin healthy individuals and most (up to 80%) episodes in patients withGERD (Tonini et al., Drugs. 2004, 64, 347-361, which is incorporatedherein by reference in its entirety).

GABA_(B) receptor agonists are also useful in promoting alcoholabstinence in alcoholics (Gessa et al., International Publication No. WO01/26638, which is incorporated herein by reference in its entirety); inpromoting smoking cessation (Gessa et al., International Publication No.WO 01/08675, which is incorporated herein by reference in its entirety);in reducing addiction liability of narcotic agents (Robson et al., U.S.Pat. No. 4,126,684, which is incorporated herein by reference in itsentirety); in the treatment of emesis (Bountra et al., U.S. Pat. No.5,719,185, which is incorporated herein by reference in its entirety);and as an anti-tussive for the treatment of cough (Kreutner et al., U.S.Pat. No. 5,006,560, which is incorporated herein by reference in itsentirety).

Typical GABA_(B) receptor agonists such as the zwitterionic4-aminobutanoic, 3-aminopropylphosphinic, 3-aminopropylphosphonous, and3-aminopropylsulfinic acids noted above are polar molecules that lackthe requisite physicochemical characteristics for effective passivepermeability across cellular membranes. For baclofen, passage of thedrug across the gastrointestinal tract and the blood-brain barrier (BBB)is mediated primarily by active transport processes, rather than bypassive diffusion. Accordingly, baclofen is a substrate for activetransport mechanisms shared by neutral α-amino acids such as leucine,and β-amino acids such as β-alanine and taurine (van Bree et al., Pharm.Res. 1988, 5, 369-371; Cercos-Fortea et al., Biopharm. Drug. Disp. 1995,16, 563-577; Deguchi et al., Pharm. Res. 1995, 12, 1838-1844; andMoll-Navarro et al., J. Pharm. Sci. 1996, 85, 1248-1254), each of whichis incorporated herein by reference in its entirety.3-Aminopropylsulfinic acids are also likely to exploit related activetransport mechanisms to permeate the gastrointestinal (GI) mucosafollowing oral administration.

Another common feature shared by baclofen and other zwitterionicGABA_(B) receptor agonists is their rapid clearance from the systemiccirculation, which leads to the necessity for frequent dosing in humans(e.g. three or four times daily) (see Bowery, supra; “Commercial andPipeline Perspectives: Upper GI Disorders,” Data Monitor Report,September 2004, p. 147). Sustained released oral dosage formulations area conventional solution to the problem of rapid systemic drug clearance,as is well known in the art (see, e.g., “Remington's PharmaceuticalSciences,” Lippincott Williams & Wilkins, 21st Edition, 2005). Osmoticdelivery systems are also recognized methods for sustained drug delivery(see, e.g., Verma et al., Drug Dev. Ind. Pharm. 2000, 26, 695-708).Successful application of these technologies depends on the drug ofinterest having an effective level of absorption from the largeintestine (also referred to herein as the colon), where the dosage formspends a majority of its time during its passage down thegastrointestinal tract. Baclofen is poorly absorbed followingadministration into the colon in animal models (Merino et al., Biopharm.Drug. Disp. 1989, 10, 279-297) presumably because the transporterproteins mediating baclofen absorption in the upper region of the smallintestine are not expressed in the large intestine. Development of anoral controlled release formulation for baclofen and other zwitterionicGABA_(B) receptor agonists should considerably improve the convenience,efficacy, and side effect profile of GABA_(B) agonist therapy. However,the rapid passage of conventional dosage forms through the proximalabsorptive region of the small intestine has thus far prevented thesuccessful application of sustained release technologies to this drug. Anumber of exploratory delivery technologies, which rely on eithermucoadhesion or gastric retention have been suggested to achievesustained delivery of baclofen (Sinnreich, U.S. Pat. No. 4,996,058;Khanna, U.S. Pat. No. 5,091,184; Fara et al., supra; Dudhara et al.,International Publication No. WO 03/011255) though to date none of theseappear to be able to achieve sustained blood levels of baclofen in humansubjects.

Thus, there is a significant need for new prodrugs of3-aminopropylsulfinic acid GABA_(B) receptor agonists which are wellabsorbed in the large intestine and/or colon and hence suitable for oralsustained release formulations, thus improving the convenience,efficacy, and side effect profile of GABA_(B) agonist therapy,particularly for the treatment of spasticity and gastroesophageal refluxdisease.

These and other needs can be satisfied by the disclosure herein ofacyloxyalkyl carbamate prodrugs of 3-aminopropylsulfinic acid andanalogs thereof, pharmaceutical compositions of acyloxyalkyl carbamateprodrugs of 3-aminopropylsulfinic acid and analogs thereof, methods ofmaking acyloxyalkyl carbamate prodrugs of 3-aminopropylsulfinic acid andanalogs thereof, and methods of using acyloxyalkyl carbamate prodrugs of3-aminopropylsulfinic acid and analogs thereof and/or pharmaceuticalcompositions thereof to treat various medical disorders.

A first aspect provides a compound of Formula (I):

stereoisomers thereof, pharmaceutically acceptable salts of any of theforegoing, pharmaceutically acceptable solvates of any of the foregoing,and combinations of any of the foregoing, wherein:

R¹ is selected from acyl, substituted acyl, alkyl, substituted alkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;

R² and R³ are independently selected from hydrogen, alkyl, substitutedalkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, cycloalkyl, substitutedcycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, andsubstituted heteroarylalkyl, or R² and R³ together with the carbon atomto which they are bonded form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, or substituted cycloheteroalkyl ring;

R⁴ is selected hydrogen, C₁₋₆ acyl, substituted C₁₋₆ acyl, C₁₋₆ alkyl,substituted C₁₋₆ alkyl, aryl, substituted aryl, C₃₋₆ cycloalkyl,substituted C₃₋₆ cycloalkyl, heteroaryl, substituted heteroaryl, C₇₋₉phenylalkyl, and substituted C₇₋₉ phenylalkyl;

R⁵ is selected from hydrogen, hydroxy, mercapto, fluoro, chloro, bromo,oxo, and 4-chlorophenyl; and

R⁶ and R⁷ are independently selected from hydrogen, C₁₋₆ alkyl,substituted C₁₋₆ alkyl, C₁₋₆ alkoxy, substituted C₁₋₆ alkoxy, aryl,substituted aryl, C₃₋₆ cycloalkyl, substituted C₃₋₆ cycloalkyl,heteroaryl, substituted heteroaryl, C₇₋₉ phenylalkyl, and substitutedC₇₋₉ phenylalkyl.

A second aspect provides methods of synthesizing a compound of Formula(I), comprising:

contacting a compound of Formula (II) and a compound of Formula (III),optionally in the presence of a base, wherein:

R⁹ and R¹⁰ are independently selected from hydrogen, acylamino, acyloxy,alkoxycarbonylamino, alkoxycarbonyloxy, alkyl, substituted alkyl,alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl,carbamoyloxy, dialkylamino, heteroaryl, hydroxy, and sulfonamido, or R⁹and R¹⁰ together with the atoms to which they are bonded form asubstituted cycloalkyl, substituted cycloheteroalkyl, or substitutedaryl ring; and

R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are as defined, supra.

A third aspect provides pharmaceutical compositions comprising at leastone compound of Formula (I), or pharmaceutically acceptable saltsthereof, or pharmaceutically acceptable solvates of any of theforegoing, and a pharmaceutically acceptable vehicle, such as a diluent,carrier, excipient, or adjuvant. The choice of diluent, carrier,excipient and adjuvant will depend upon, among other factors, thedesired mode of administration.

A fourth aspect provides methods of treating or preventinggastroesophageal reflux disease. Methods are also provided for treatingor preventing spasticity, alcohol abuse or addiction, nicotine abuse oraddiction, narcotics abuse or addiction, emesis, and cough. The methodsgenerally involve administering to a patient in need of such treatmentor prevention a therapeutically effective amount of at least onecompound of Formula (I) and/or a pharmaceutical composition thereof.

DEFINITIONS

Unless otherwise indicated, all numbers expressing quantities ofingredients, reaction conditions, and so forth used in the specificationand claims are to be understood as being modified in all instances bythe term “about” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in the following specification andattached claims are approximations that may vary depending upon theproperties sought to be obtained. At the very least, each numericalparameter should at least be construed in light of the number ofreported significant digits and by applying ordinary roundingtechniques.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the embodiments are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical values, however, inherently contain certainerrors necessarily resulting form the standard deviation found in theirrespective testing measurements.

The section headings used herein are for organizational purposes only,and are not to be construed as limiting the subject matter disclosed.

To the extent the definitions of terms in the publications, patents, andpatent applications incorporated herein by reference are not the same asthe definitions set forth in this specification, the definitions in thisspecification control for the entire specification, including theclaims. Any other definitions in the publications, patents, and patentapplications incorporated herein by reference that are not explicitlyprovided in this specification apply only to the embodiments discussedin the publications, patents, and patent applications incorporatedherein by reference.

“1-Acyloxy-alkyl carbamate” refers to an N-1-acyloxy-alkoxycarbonylderivative of 3-aminopropylsulfinic acid or analog thereof asencompassed by compounds of Formula (I).

“Alkyl” by itself or as part of another substituent refers to asaturated or unsaturated, branched, straight-chain, or cyclic monovalenthydrocarbon radical derived by the removal of one hydrogen atom from asingle carbon atom of a parent alkane, alkene, or alkyne. Typical alkylgroups include, but are not limited to, methyl; ethyls such as ethanyl,ethenyl, and ethynyl; propyls such as propan-1-yl, propan-2-yl,cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl(allyl), cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yn-1-yl,prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl,2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

The term “alkyl” is specifically intended to include groups having anydegree or level of saturation, i.e., groups having exclusively singlecarbon-carbon bonds, groups having one or more double carbon-carbonbonds, groups having one or more triple carbon-carbon bonds, and groupshaving mixtures of single, double, and triple carbon-carbon bonds. Wherea specific level of saturation is intended, the expressions “alkanyl,”“alkenyl,” and “alkynyl” are used. In certain embodiments, an alkylgroup comprises from 1 to 20 carbon atoms, in certain embodiments, from1 to 10 carbon atoms, and in certain embodiments, from 1 to 6 carbonatoms.

“Alkanyl” by itself or as part of another substituent refers to asaturated branched, straight-chain, or cyclic alkyl radical derived bythe removal of one hydrogen atom from a single carbon atom of a parentalkane. Examples of alkanyl groups include, but are not limited to,methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl(isopropyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl,butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl),2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like.

“Alkenyl” by itself or as part of another substituent refers to anunsaturated branched, straight-chain, or cyclic alkyl radical having atleast one carbon-carbon double bond derived by the removal of onehydrogen atom from a single carbon atom of a parent alkene. The groupmay be in either the cis or trans conformation about the double bond(s).Examples of alkenyl groups include, but are not limited to, ethenyl;propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl(allyl), prop-2-en-2-yl, and cycloprop-1-en-1-yl; cycloprop-2-en-1-yl;butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl,but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl,buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl,cyclobuta-1,3-dien-1-yl, etc.; and the like.

“Alkynyl” by itself or as part of another substituent refers to anunsaturated branched, straight-chain, or cyclic alkyl radical having atleast one carbon-carbon triple bond derived by the removal of onehydrogen atom from a single carbon atom of a parent alkyne. Examples ofalkynyl groups include, but are not limited to, ethynyl; propynyls suchas prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl,but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

“Acyl” by itself or as part of another substituent refers to a radical,—C(O)R³⁰, where R³⁰ is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl,aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl as definedherein. Examples include, but are not limited to formyl, acetyl,cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl,and the like.

“Alkoxy” by itself or as part of another substituent refers to a radical—OR³¹ where R³¹ represents an alkyl or cycloalkyl group as definedherein. Examples include, but are not limited to, methoxy, ethoxy,propoxy, butoxy, cyclohexyloxy, and the like.

“Alkoxycarbonyl” by itself or as part of another substituent refers to aradical —C(O)OR³¹ where R³¹ represents an alkyl or cycloalkyl group asdefined herein. Examples include, but are not limited to,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,cyclohexyloxycarbonyl, and the like.

“3-Aminopropylsulfinic acid analog” refers to a compound of Formula(II):

wherein:

R⁴ is selected from hydrogen, C₁₋₆ acyl, substituted C₁₋₆ acyl, C₁₋₆alkyl, substituted C₁₋₆ alkyl, aryl, substituted aryl, C₃₋₆ cycloalkyl,substituted C₃₋₆ cycloalkyl, heteroaryl, substituted heteroaryl, C₇₋₉phenylalkyl, and substituted C₇₋₉ phenylalkyl.

R⁵ is selected from hydrogen, hydroxy, mercapto, fluoro, chloro, bromo,oxo, and 4-chlorophenyl; and

R⁶ and R⁷ are independently selected from hydrogen, C₁₋₆ alkylsubstituted C₁₋₆ alkyl, C₁₋₆ alkoxy, substituted C₁₋₆ alkoxy, aryl,substituted aryl, C₃₋₆ cycloalkyl, substituted C₃₋₆ cycloalkyl,heteroaryl, substituted heteroaryl, C₇₋₉ phenylalkyl, and substitutedC₇₋₉ phenylalkyl.

Within the scope of this disclosure, it is to be understood that when R⁵is an oxo group the bond between R⁵ and the carbon to which it is bondedis a double bond.

“Aryl” by itself or as part of another substituent refers to amonovalent aromatic hydrocarbon radical derived by the removal of onehydrogen atom from a single carbon atom of a parent aromatic ringsystem. Examples of aryl groups include, but are not limited to, groupsderived from aceanthrylene, acenaphthylene, acephenanthrylene,anthracene, azulene, benzene, chrysene, coronene, fluoranthene,fluorene, hexacene, hexaphene, hexylene, as-indacene, s-indacene,indane, indene, naphthalene, octacene, octaphene, octalene, ovalene,penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene,phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene,triphenylene, trinaphthalene, and the like. In certain embodiments, anaryl group comprises from 6 to 20 carbon atoms, and in certainembodiments, from 6 to 12 carbon atoms.

“Arylalkyl” by itself or as part of another substituent refers to anacyclic alkyl radical in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced withan aryl group. Typical arylalkyl groups include, but are not limited to,benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl,2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl, and the like. Where specific alkyl moietiesare intended, the nomenclature arylalkanyl, alkylalkenyl, and/orarylalkynyl is used. In certain embodiments, an arylalkyl group is C₇₋₃₀arylalkyl, e.g., the alkanyl, alkenyl, or alkynyl moiety of thearylalkyl group is C₁₋₁₀ and the aryl moiety is C₆₋₂₀, and in certainembodiments, an arylalkyl group is C₇₋₂₀ arylalkyl, e.g., the alkanyl,alkenyl, or alkynyl moiety of the arylalkyl group is C₁-8 and the arylmoiety is C₆₋₁₂.

“AUC” is the area under a curve representing the concentration of acompound or metabolite thereof in a biological fluid in a patient as afunction of time following administration of the compound to thepatient. In certain embodiments, the compound can be a prodrug and themetabolite can be a drug. Examples of biological fluids include plasmaand blood. The AUC can be determined by measuring the concentration of acompound or metabolite thereof in a biological fluid such as the plasmaor blood using methods such as liquid chromatography-tandem massspectrometry (LC/MS/MS), at various time intervals, and calculating thearea under the plasma concentration-versus-time curve. Suitable methodsfor calculating the AUC from a drug concentration-versus-time curve arewell known in the art. As relevant to the disclosure here, an AUC for3-aminopropylsulfinic acid or analogs thereof can be determined bymeasuring the concentration of 3-aminopropylsulfinic acid or analogsthereof in the plasma or blood of a patient following oraladministration of a compound of Formula (I) to the patient.

“Bioavailability” refers to the rate and amount of a drug that reachesthe systemic circulation of a patient following administration of thedrug or prodrug thereof to the patient and can be determined byevaluating, for example, the plasma or blood concentration-versus-timeprofile for the drug. Parameters useful in characterizing a plasma orblood concentration-versus-time curve include the area under the curve(AUC), the time to peak concentration (T_(max)), and the maximum drugconcentration (C_(max)).

“Bioequivalence” refers to equivalence of the rate and extent ofabsorption of a drug after administration of equal doses of the drug orprodrug to a patient. As used herein, two plasma or blood concentrationprofiles are bioequivalent if the 90% confidence interval for the ratioof the mean response of the two profiles is within the limits of 0.8 and1.25. The mean response includes at least one of the characteristicparameters of a profile such as C_(max), T_(max), and AUC.

“C_(max)” is the maximum concentration of a drug in the plasma or bloodof a patient following administration of a dose of the drug or prodrugto the patient.

“T_(max)” is the time to the maximum concentration (C_(max)) of a drugin the plasma or blood of a patient following administration of a doseof the drug or prodrug to the patient.

“Compounds of the Present disclosure” refers to compounds encompassed bystructural Formula (I) and includes specific compounds disclosed hereinencompassed by Formula (I). Compounds may be identified either by theirchemical structure and/or chemical name. When the chemical structure andchemical name conflict, the chemical structure is determinative of theidentity of the compound. The compounds described herein may contain oneor more chiral centers and/or double bonds and therefore, may exist asstereoisomers, such as double-bond isomers (i.e., geometric isomers),enantiomers, or diastereomers. Accordingly, the chemical structuresdisclosed herein encompass all possible enantiomers and stereoisomers ofthe illustrated compounds including the stereoisomerically pure form(e.g., geometrically pure, enantiomerically pure, or diastereomericallypure) and enantiomeric and stereoisomeric mixtures. Enantiomeric andstereoisomeric mixtures can be resolved into their component enantiomersor stereoisomers using separation techniques or chiral synthesistechniques well known to the skilled artisan. The compounds may alsoexist in several tautomeric forms including the enol form, the ketoform, and mixtures thereof. Accordingly, the chemical structuresdepicted herein encompass all possible tautomeric forms of theillustrated compounds. The disclosed compounds also include isotopicallylabeled compounds where one or more atoms have an atomic mass differentfrom the atomic mass conventionally found in nature. Examples ofisotopes that may be incorporated into the compounds of the presentdisclosure include, but are not limited to, ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N,¹³O, ¹⁷O, etc. Compounds may exist in unsolvated forms as well assolvated forms, including hydrated forms and as N-oxides. In general,compounds may be hydrated, solvated, or N-oxides. Certain compounds mayexist in multiple crystalline or amorphous forms. In general, allphysical forms are equivalent for the uses contemplated herein and areintended to be within the scope of the present disclosure. Further, whenpartial structures of the compounds are illustrated, brackets indicatethe point of attachment of the partial structure to the rest of themolecule.

“Corresponding prodrug of 3-aminopropylsulfinic acid or analog thereof”refers to a compound of Formula (I) having the same R⁴, R⁵, R⁶, and R⁷substituents as the 3-aminopropylsulfinic acid or analog thereof ofFormula (II). Likewise, the “corresponding 3-aminopropylsulfinic acid oranalog thereof” refers to a compound of Formula (II) having the same R⁴,R⁵, R⁶, and R⁷ substituents as the prodrug of 3-aminopropylsulfinic acidor analog thereof of Formula (I). A compound of Formula (II) can haveone or more corresponding prodrugs of Formula (I). A prodrug of Formula(I) has a single corresponding 3-aminopropylsulfinic acid or analogthereof of Formula (II).

“Cycloalkoxycarbonyl” by itself or as part of another substituent refersto a radical —C(O)OR³⁶ where R³⁶ represents an cycloalkyl group asdefined herein. Representative examples include, but are not limited to,cyclobutyloxycarbonyl, cyclohexyloxycarbonyl, and the like.

“Cycloalkyl” by itself or as part of another substituent refers to asaturated or unsaturated cyclic alkyl radical. Where a specific level ofsaturation is intended, the nomenclature “cycloalkanyl” or“cycloalkenyl” is used. Examples of cycloalkyl groups include, but arenot limited to, groups derived from cyclopropane, cyclobutane,cyclopentane, cyclohexane, and the like. In certain embodiments, acycloalkyl group is C₃₋₁₀ cycloalkyl, and in certain embodiments, C₃₋₇cycloalkyl.

“Cycloheteroalkyl” by itself or as part of another substituent refers toa saturated or unsaturated cyclic alkyl radical in which one or morecarbon atoms (and any associated hydrogen atoms) are independentlyreplaced with the same or different heteroatom. Examples of heteroatomsto replace a carbon atom(s) include, but are not limited to, N, P, O, S,Si, etc. Where a specific level of saturation is intended, thenomenclature “cycloheteroalkanyl” or “cycloheteroalkenyl” is used.Cycloheteroalkyl groups include, but are not limited to, groups derivedfrom epoxides, azirines, thiiranes, imidazolidine, morpholine,piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, and thelike.

“Heteroalkyl, heteroalkanyl, heteroalkenyl, and heteroalkynyl” bythemselves or as part of another substituent refer to alkyl, alkanyl,alkenyl, and alkynyl groups, respectively, in which one or more of thecarbon atoms (and any associated hydrogen atoms) are independentlyreplaced with the same or different heteroatomic groups. Examples ofheteroatomic groups which can be included in these groups include, butare not limited to, —O—, —S—, —O—O—, —S—S—, —O—S—, —NR³⁷R³⁸—, ═N—N═,—N═N—, —N═N—NR³⁹R⁴⁰, —PR⁴¹—, —P(O)₂—, —POR⁴²—, —O—P(O)₂—, —SO—, —SO₂—,—SnR⁴³R⁴⁴—, and the like, where R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, andR⁴⁴ are independently selected from hydrogen, alkyl, substituted alkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

“Heteroaryl” by itself or as part of another substituent, refers to amonovalent heteroaromatic radical derived by the removal of one hydrogenatom from a single atom of a parent heteroaromatic ring system. Examplesof heteroaryl groups include, but are not limited to, groups derivedfrom acridine, arsindole, carbazole, β-carboline, chromane, chromene,cinnoline, furan, imidazole, indazole, indole, indoline, indolizine,isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and thelike. In certain embodiments, a heteroaryl group is from 5-20 memberedheteroaryl, and in certain embodiments from 5-10 membered heteroaryl. Incertain embodiments, a heteroaryl group is derived from thiophene,pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline,imidazole, oxazole, and pyrazine.

“Heteroarylalkyl” by itself or as part of another substituent refers toan acyclic alkyl radical in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced with aheteroaryl group. Where specific alkyl moieties are intended, thenomenclature heteroarylalkanyl, heteroarylalkenyl, and/orheterorylalkynyl is used. In certain embodiments, a heteroarylalkylgroup is a 6-30 membered heteroarylalkyl, e.g., the alkanyl, alkenyl, oralkynyl moiety of the heteroarylalkyl is 1-10 membered and theheteroaryl moiety is a 5-20-membered heteroaryl, and in certainembodiments, a 6-20 membered heteroarylalkyl, e.g., the alkanyl,alkenyl, or alkynyl moiety of the heteroarylalkyl is 1-8 membered andthe heteroaryl moiety is a 5-12-membered heteroaryl.

“Immediately preceding embodiments” refers to the embodiments disclosedin the paragraph.

“Parent aromatic ring system” refers to an unsaturated cyclic orpolycyclic ring system having a conjugated π electron system.Specifically included within the definition of “parent aromatic ringsystem” are fused ring systems in which one or more of the rings arearomatic and one or more of the rings are saturated or unsaturated, suchas, for example, fluorene, indane, indene, phenalene, etc. Examples ofparent aromatic ring systems include, but are not limited to,aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene,benzene, chrysene, coronene, fluoranthene, fluorene, hexacene,hexaphene, hexylene, as-indacene, s-indacene, indane, indene,naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene,pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene,picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene,trinaphthalene, and the like.

“Parent heteroaromatic ring system” refers to a parent aromatic ringsystem in which one or more carbon atoms (and any associated hydrogenatoms) are independently replaced with the same or different heteroatom.Examples of heteroatoms to replace the carbon atoms include, but are notlimited to, N, P, O, S, Si, etc. Specifically included within thedefinition of “parent heteroaromatic ring systems” are fused ringsystems in which one or more of the rings are aromatic and one or moreof the rings are saturated or unsaturated, such as, for example,arsindole, benzodioxan, benzofuran, chromane, chromene, indole,indoline, xanthene, etc. Examples of parent heteroaromatic ring systemsinclude, but are not limited to, arsindole, carbazole, β-carboline,chromane, chromene, cinnoline, furan, imidazole, indazole, indole,indoline, indolizine, isobenzofuran, isochromene, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline,phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline,quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,thiophene, triazole, xanthene, and the like.

“Patient” refers to a mammal, for example, a human.

“Pharmaceutically acceptable” refers to approved or approvable by aregulatory agency of the Federal or state government or listed in theU.S. Pharmacopoeia or other generally recognized pharmacopoeia for usein animals and more particularly in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound, whichpossesses the desired pharmacological activity of the parent compound.Such salts include: (1) acid addition salts, formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound isreplaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine, andthe like.

“Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant,excipient, or carrier with which a compound is administered.

“Pharmaceutical composition” refers to at least one compound and atleast one pharmaceutically acceptable vehicle, with which the compoundis administered to a patient.

“Preventing” or “prevention” refers to a reduction in risk of acquiringa disease or disorder (i.e., causing at least one of the clinicalsymptoms of the disease not to develop in a patient that may be exposedto or predisposed to the disease but does not yet experience or displaysymptoms of the disease).

“Prodrug” refers to a derivative of a drug molecule that requires atransformation within the body to release the active drug. Compounds ofFormula (I) are prodrugs that can be metabolized within a patient's bodyto form the corresponding parent drug, 3-aminopropylsulfinic acid oranalogs thereof having Formula (II), and hence compounds of Formula (I)are prodrugs of the corresponding 3-aminopropylsulfinic acid or analogsthereof having Formula (II). Compounds of Formula (I) includepharmaceutically acceptable salts thereof, or pharmaceuticallyacceptable solvates of the free acid form of any of the foregoing, aswell as crystalline forms of any of the foregoing. Prodrugs arefrequently, although not necessarily, pharmacologically inactive untilconverted to the parent drug.

“Promoiety” refers to a form of protecting group that when used to maska functional group within a drug molecule converts the drug into aprodrug. Typically, the promoiety will be attached to the drug viabond(s) that are cleaved by enzymatic or non-enzymatic means in vivo.

“Protecting group” refers to a grouping of atoms, which when bonded to areactive functional group in a molecule masks, reduces, or preventsreactivity of the functional group. Examples of protecting groups can befound in Green et al., “Protective Groups in Organic Chemistry”, (Wiley,2^(nd) ed. 1991) and Harrison et al., “Compendium of Synthetic OrganicMethods”, Vols. 1-8 (John Wiley and Sons, 1971-1996). Examples of aminoprotecting groups include, but are not limited to, formyl, acetyl,trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl(Boc), trimethylsilyl (TMS), 2-trimethylsilyl-ethanesulfonyl (SES),trityl and substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl (NVOC),and the like. Examples of hydroxy protecting groups include, but are notlimited to, those where the hydroxy group is either acylated oralkylated such as benzyl, and trityl ethers as well as alkyl ethers,tetrahydropyranyl ethers, triallylsilyl ethers, and allyl ethers.

“Solvate” refers to a molecular complex of a compound with one or moresolvent molecules in a stoichiometric or non-stoichiometric amount. Suchsolvent molecules are those commonly used in the pharmaceutical art,which are known to be innocuous to a recipient, e.g., water, ethanol,and the like. A molecular complex of a compound or moiety of a compoundand a solvent can be stabilized by non-covalent intra-molecular forcessuch as, for example, electrostatic forces, van der Waals forces, orhydrogen bonds. The term “hydrate” refers to a complex where the one ormore solvent molecules are water.

“Stereoisomers” refers to isomers that differ in the arrangement of theconstituent atoms in space, and includes enantiomers and diastereomers.Stereoisomers that are mirror images of each other and optically activeare termed “enantiomers,” and stereoisomers that are not mirror imagesof one another are termed “diastereoisomers.”

“Sustained release” refers to release of a compound of Formula (I) froma dosage form at a rate effective to achieve a therapeutic orprophylactic concentration of the compound of Formula (I), or activemetabolite thereof, in the systemic blood circulation over a prolongedperiod of time relative to that achieved by oral administration of animmediate release formulation of the compound of Formula (I). In someembodiments, release of a compound of Formula (I) occurs over a periodof at least about 4 hours, such as at least about 8 hours, in someembodiments, at least about 12 hours, at least about 16 hours, at leastabout 20 hours, and in some embodiments, at least about 24 hours.

“Substantially one diastereomer” refers to a compound containing two ormore stereogenic centers such that the diastereomeric excess (d.e.) ofthe compound is at least about 90%. The diastereomeric excess is theratio of the percentage of one diastereomer in a mixture to that ofanother diastereomer. In some embodiments, the diastereomeric excess is,for example, at least about 91%, at least about 92%, at least about 93%,at least about 94%, at least about 95%, at least about 96%, at leastabout 97%, at least about 98%, or at least about 99%.

“Substituted” refers to a group in which one or more hydrogen atoms areindependently replaced with the same or different substituent(s).Typical substituents include, but are not limited to, -M, —R⁶⁰, —O⁻, ═O,—OR⁶⁰, —S⁶⁰, —S⁻, ═S, —NR⁶⁰R⁶¹, ═NR⁶⁰, —CF₃, —CN, —OCN, —SCN, —NO, —NO₂,═N₂, —N₃, —S(O)₂O⁻, —S(O)₂OH, —S(O)₂R⁶⁰, —OS(O₂)O⁻, —OS(O)₂R⁶⁰,—P(O)(O⁻)₂, —P(O)(OR⁶⁰)(O⁻), —OP(O)(OR⁶⁰)(OR⁶¹), —C(O)R⁶⁰, —C(S)R⁶⁰,C(O)OR⁶⁰, —C(O)NR⁶⁰R⁶¹, —C(O)O⁻, —C(S)OR⁶⁰, —NR⁶²C(O)NR⁶⁰R⁶¹,—NR⁶²C(S)NR⁶⁰R⁶¹, —NR⁶²C(NR⁶³)NR⁶⁰R⁶¹, and —C(NR⁶²)NR⁶⁰R⁶¹ where M isindependently a halogen; R⁶⁰, R⁶¹, R⁶², and R⁶³ are independentlyhydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, aryl, substituted aryl, heteroaryl, or substitutedheteroaryl, or R⁶⁰ and R⁶¹ together with the nitrogen atom to which theyare bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.In certain embodiments, substituents include -M, —R⁶⁰, ═O, —OR⁶⁰, —SR⁶⁰,—S⁻, ═S, —NR⁶⁰R⁶¹, ═NR⁶⁰, —CF₃, —CN, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃,—S(O)₂R⁶⁰, —OS(O₂)O⁻, —OS(O)₂R⁶⁰, —P(O)(O⁻)₂, —P(O)(OR⁶⁰)(O⁻),—OP(O)(OR⁶⁰)(OR⁶¹), —C(O)R⁶⁰, C(S)⁶⁰, —C(O)OR⁶⁰, —C(O)NR⁶⁰R⁶¹, —C(O)O⁻,and —NR⁶²C(O)NR⁶⁰R⁶¹, in certain embodiments, -M, —R⁶⁰, ═O, —OR⁶⁰,—SR⁶⁰, —NR⁶⁰R⁶¹, CF₃, —CN, —NO₂, —S(O)₂R⁶⁰, —P(O)(OR⁶⁰)(O⁻),—OP(O)(OR⁶⁰)(OR⁶¹), —C(O)R⁶⁰, —C(O)OR⁶⁰, —C(O)NR⁶⁰R⁶¹, and —C(O)O⁻, andin certain embodiments, -M, —R⁶⁰, ═O, —OR⁶⁰, —SR⁶⁰, —NR⁶⁰R⁶¹, —CF₃, —CN,—NO₂, —S(O)₂R⁶⁰, —OP(O)(OR⁶⁰)(OR⁶¹), —C(O)R⁶⁰, —C(O)OR⁶⁰, and —C(O)O⁻,where R⁶⁰, R⁶¹, and R⁶² are as defined above.

“Treating” or “treatment” of any disease or disorder refers, in someembodiments, to ameliorating at least one disease or disorder (i.e.,arresting or reducing the development of the disease or at least one ofthe clinical symptoms thereof). In certain embodiments “treating” or“treatment” refers to ameliorating at least one physical parameter,which may or may not be discernible by the patient. In certainembodiments, “treating” or “treatment” refers to inhibiting the diseaseor disorder, either physically, (e.g., stabilization of a discerniblesymptom), physiologically, (e.g., stabilization of a physicalparameter), or both. In certain embodiments, “treating” or “treatment”refers to delaying the onset of the disease or disorder.

“Therapeutically effective amount” means the amount of compound that,when administered to a patient for treating or preventing a disease, issufficient to effect such treatment or prevention of the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity, and the age, weight, etc., of the patienthaving the disease to be treated or prevented.

Reference will now be made in detail to certain embodiments of compoundsand methods. The disclosed embodiments are not intended to be limitingof the claims. To the contrary, the claims are intended to cover allalternatives, modifications, and equivalents of the disclosedembodiments.

Compounds

Certain embodiments provide a compound of Formula (I):

stereoisomers thereof, pharmaceutically acceptable salts of any of theforegoing, pharmaceutically acceptable solvates of any of the foregoing,and combinations of any of the foregoing, wherein:

R¹ is selected from acyl, substituted acyl, alkyl substituted alkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;

R² and R³ are independently selected from hydrogen, alkyl, substitutedalkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, cycloalkyl, substitutedcycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, andsubstituted heteroarylalkyl, or R¹ and R³ together with the carbon atomto which they are bonded form a cycloalkyl, substituted 6-cycloalkyl,cycloheteroalkyl, or substituted cycloheteroalkyl ring;

R⁴ is selected from hydrogen, C₁₋₆ acyl, substituted C₁₋₆ acyl, C₁₋₆alkyl, substituted C₁₋₆ alkyl, aryl, substituted aryl, C₃₋₆ cycloalkyl,substituted C₃₋₆ cycloalkyl, heteroaryl, substituted heteroaryl, C₇₋₉phenylalkyl, and substituted C₇₋₉ phenylalkyl;

R⁵ is selected from hydrogen, hydroxy, mercapto, fluoro, chloro, bromo,oxo, and 4-chlorophenyl; and

R⁶ and R⁷ are independently selected from hydrogen, C₁₋₆ alkyl,substituted C₁₋₆ alkyl, C₁₋₆ alkoxy, substituted C₁₋₄ alkoxy, aryl,substituted aryl, C₃₋₆ cycloalkyl, substituted C₃₋₆ cycloalkyl,heteroaryl, substituted heteroaryl, C₇₋₉ phenylalkyl, and substitutedC₇₋₉ phenylalkyl.

Within the scope of this disclosure, it is to be understood that when R⁵is an oxo group the bond between R⁵ and the carbon to which it is bondedis a double bond.

In certain embodiments, each of R⁴, R⁶, and R⁷ are hydrogen.

In certain embodiments, R⁵ is selected from hydrogen, hydroxy, fluoro,oxo, and 4-chlorophenyl. In certain embodiments, R⁵ is selected fromhydrogen, hydroxy, fluoro, oxo, and 4-chlorophenyl, and each of R⁴, R⁶,and R⁷ is hydrogen.

In certain embodiments of compounds of Formula (I), the carbon to whichR⁵ is attached is of the R configuration. In certain embodiments ofcompounds of Formula (I), the carbon to which R⁵ is attached is of the Sconfiguration.

In certain embodiments of compounds of Formula (I), R⁵ is selected fromhydrogen, hydroxy, fluoro, oxo, and 4-chlorophenyl, and each of R⁴, R⁶,and R⁷ is hydrogen. In certain embodiments, R⁵ is hydrogen, and each ofR⁴, R⁶, and R⁷ is hydrogen. In certain embodiments, R⁵ is oxo, and eachof R⁴, R⁶, and R⁷ is hydrogen. In certain embodiments, R⁵ is hydroxy,and each of R⁴, R⁶, and R⁷ is hydrogen. In certain embodiments, R⁵ ishydroxy, and each of R⁴, R⁶, and R⁷ is hydrogen, and the carbon to whichR⁵ is bonded is of the R configuration. In certain embodiments, R⁵ ishydroxy, and each of R⁴, R⁶, and R⁷ is hydrogen, and the carbon to whichR⁵ is bonded is of the S configuration. In certain embodiments, R⁵ isfluoro, and each of R⁴, R⁶, and R⁷ is hydrogen. In certain embodiments,R⁵ is fluoro, and each of R⁴, R⁶, and R⁷ is hydrogen, and the carbon towhich R⁵ is bonded is of the R configuration. In certain embodiments, R⁵is fluoro, and each of R⁴, R⁶, and R⁷ is hydrogen, and the carbon towhich R⁵ is bonded is of the S configuration. In certain embodiments, R⁵is 4-chlorophenyl, and each of R⁴, R⁶, and R⁷ is hydrogen. In certainembodiments, R⁵ is 4-chlorophenyl, and each of R⁴, R⁶, and R⁷ ishydrogen, and the carbon to which R¹ is bonded is of the Rconfiguration. In certain embodiments, R⁵ is 4-chlorophenyl, and each ofR⁴, R⁶, and R⁷ is hydrogen, and the carbon to which R⁵ is bonded is ofthe S configuration.

In certain embodiments of compounds of Formula (I), R¹ is selected fromC₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, substitutedphenyl, C₇₋₉ phenylalkyl, and pyridyl. In certain embodiments ofcompounds of Formula (I), R¹ is selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 2-pyridyl, 3-pyridyl, and4-pyridyl. In certain embodiments of compounds of Formula (I), R¹ isselected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-diethoxyethyl, phenyl, cyclohexyl, and 3-pyridyl.

In certain embodiments of compounds of Formula (I), R² and R³ areindependently selected from hydrogen, alkyl, substituted alkyl,alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substitutedcycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl. In certain embodiments of compounds of Formula (I), R²and R³ are independently selected from hydrogen, C₁₋₄ alkyl, substitutedC₁₋₄ alkyl, C₁₋₄ alkoxycarbonyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkoxycarbonyl, phenyl, substituted phenyl, C₇₋₉ phenylalkyl, andpyridyl. In certain embodiments of compounds of Formula (I), R² and R³are independently selected from hydrogen, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl,cyclohexyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl,cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl, 2-pyridyl, 3-pyridyl,and 4-pyridyl. In certain embodiments of compounds of Formula (I), R² isselected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl,methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl,cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl, 2-pyridyl, 3-pyridyl,and 4-pyridyl, and R³ is hydrogen. In certain embodiments of compoundsof Formula (I), R² is selected from hydrogen, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, phenyl, and cyclohexyl, and R³is hydrogen. In certain embodiments of compounds of Formula (I), R² isselected from methyl, methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, and cyclohexyloxycarbonyl, and R³ is methyl

In certain embodiments of compounds of Formula (I), R² and R³ togetherwith the carbon atom to which they are bonded form a cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, or substitutedcycloheteroalkyl ring. In certain embodiments of compounds of Formula(I), R² and R³ together with the carbon atom to which they are bondedform a cyclobutyl, cyclopentyl, or cyclohexyl ring.

In certain embodiments of compounds of Formula (I), R¹ is selected fromC₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, substitutedphenyl, C₇₋₉ phenylalkyl, and pyridyl, and R² and R³ are independentlyselected from hydrogen, C₁₋₄ alkyl, substituted C₁₋₄ alkyl, C₁₋₄alkoxycarbonyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkoxycarbonyl, phenyl,substituted phenyl, C₇₋₉ phenylalkyl, and pyridyl. In certainembodiments where R² and R³ are independently selected from hydrogen,C₁₋₄ alkyl, substituted C₁₋₄ alkyl, C₁₋₄ alkoxycarbonyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkoxycarbonyl, phenyl, substituted phenyl, C₇₋₉phenylalkyl, and pyridyl, R¹ is selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 2-pyridyl, 3-pyridyl, and4-pyridyl, and in certain embodiments, R¹ is selected from methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-diethoxyethyl, phenyl,cyclohexyl, and 3-pyridyl. In certain of the immediately precedingembodiments of compounds of Formula (I), R⁵ is selected from hydrogen,hydroxy, fluoro, oxo, and 4-chlorophenyl.

In certain embodiments of compounds of Formula (I), R¹ is selected fromC₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, substitutedphenyl, C₇₋₉ phenylalkyl, and pyridyl, and R² and R³ are independentlyselected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl,methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl,cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl, 2-pyridyl, 3-pyridyl,and 4-pyridyl. In certain of the embodiments where R² and R³ areindependently selected from hydrogen, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl,cyclohexyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl,cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl, 2-pyridyl, 3-pyridyl,and 4-pyridyl, R¹ is selected from methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl, and incertain embodiments, R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-diethoxyethyl, phenyl, cyclohexyl, and 3-pyridyl. Incertain of the immediately preceding embodiments of compounds of Formula(I), R⁵ is selected from hydrogen, hydroxy, fluoro, oxo, and4-chlorophenyl, and each of R⁴, R⁶, and R⁷ are hydrogen.

In certain embodiments of compounds of Formula (I), R¹ is selected fromC₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, substitutedphenyl, C₇₋₉ phenylalkyl, and pyridyl, R² is selected from hydrogen,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,phenyl, and cyclohexyl, and R³ is hydrogen. In certain embodiments, R¹is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-dimethoxyethyl, 1,1-diethoxyethyl, phenyl, 4-methoxyphenyl, benzyl,phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,2-pyridyl, 3-pyridyl, and 4-pyridyl, R² is selected from hydrogen,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,phenyl, and cyclohexyl, and R³ is hydrogen. In certain embodiments, R¹is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-diethoxyethyl, phenyl, cyclohexyl, and 3-pyridyl, R² is selectedfrom hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, phenyl, and cyclohexyl, and R³ is hydrogen. In certain of theimmediately preceding embodiments of compounds of Formula (I), R⁵ isselected from hydrogen, hydroxy, fluoro, oxo, and 4-chlorophenyl, andeach of R⁴, R⁶, and R⁷ is hydrogen.

In certain embodiments of compounds of Formula (I), R¹ is selected fromC₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, substitutedphenyl, C₇₋₉ phenylalkyl, and pyridyl, R² is selected from methyl,methoxycarbonyl, ethoxycarbonyl, isopropoxy carbonyl, andcyclohexyloxycarbonyl, and R³ is methyl. In certain embodiments, R¹ isselected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-dimethoxyethyl, 1,1-diethoxyethyl, phenyl, 4-methoxyphenyl, benzyl,phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,2-pyridyl, 3-pyridyl, and 4-pyridyl, R² is selected from methyl,methoxycarbonyl, ethoxycarbonyl, isopropoxy carbonyl, andcyclohexyloxycarbonyl, and R³ is methyl. In certain embodiments, R¹ isselected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl neopentyl,1,1-diethoxyethyl, phenyl, cyclohexyl, and 3-pyridyl, R² is selectedfrom methyl, methoxycarbonyl, ethoxycarbonyl, isopropoxy carbonyl, andcyclohexyloxycarbonyl, and R³ is methyl. In certain of the immediatelypreceding embodiments of compounds of Formula (I), R⁵ is selected fromhydrogen, hydroxy, fluoro, oxo, and 4-chlorophenyl, and each of R⁴, R⁶,and R⁷ is hydrogen.

In certain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-diethoxyethyl, phenyl, cyclohexyl, 2-pyridyl, 3-pyridyl, and4-pyridyl, R⁷ is selected from hydrogen, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, phenyl, and cyclohexyl, R³ ishydrogen, R⁵ is hydrogen, and each of R⁴, R⁶, and R⁷ is hydrogen. Incertain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-diethoxyethyl, phenyl, cyclohexyl, 2-pyridyl, 3-pyridyl, and4-pyridyl, R² is selected from hydrogen, methyl, n-propyl, andisopropyl, R³ is hydrogen, R⁵ is hydrogen, and each of R⁴, R⁶, and R⁷ ishydrogen. In certain embodiments of compounds of Formula (I), R¹ isselected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² is selectedfrom hydrogen, methyl, n-propyl, and isopropyl, R³ is hydrogen, R⁵ ishydrogen, and each of R⁴, R⁶, and R⁷ is hydrogen.

In certain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-diethoxyethyl, phenyl, cyclohexyl, 2-pyridyl, 3-pyridyl, and4-pyridyl, R² is selected from methyl, methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, and cyclohexyloxycarbonyl, R³ is methyl, R⁵ ishydrogen, and each of R⁴, R⁶, and R⁷ is hydrogen.

In certain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² is hydrogen, R³ ishydrogen, R⁵ is hydrogen, and each of R⁴, R⁶, and R⁷ is hydrogen. Incertain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² is methyl, R³ ishydrogen, R⁵ is hydrogen, and each of R⁴, R⁶, and R⁷ is hydrogen. Incertain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² is n-propyl, R³ ishydrogen, R⁵ is hydrogen, and each of R⁴, R⁶, and R⁷ is hydrogen. Incertain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² is isopropyl, R³ ishydrogen, R⁵ is hydrogen, and each of R⁴, R⁶, and R⁷ is hydrogen.

In certain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-diethoxyethyl, phenyl, cyclohexyl, 2-pyridyl, 3-pyridyl, and4-pyridyl, R² is selected from hydrogen, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, phenyl, and cyclohexyl, R³ ishydrogen, R⁵ is hydroxy, and each of R⁴, R⁶, and R⁷ is hydrogen. Incertain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-diethoxyethyl, phenyl, cyclohexyl, 2-pyridyl, 3-pyridyl, and4-pyridyl, R² is selected from hydrogen, methyl, n-propyl, andisopropyl, R³ is hydrogen, R⁵ is hydroxy, and each of R⁴, R⁶, and R⁷ ishydrogen. In certain embodiments of compounds of Formula (I), R¹ isselected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² is selectedfrom hydrogen, methyl, n-propyl, and isopropyl, R³ is hydrogen, R⁵ ishydroxy, and each of R⁴, R⁶, and R⁷ is hydrogen. In certain of theimmediately preceding embodiments of compounds of Formula (I), thecarbon to which R⁵ is bonded is of the R configuration. In certain ofthe immediately preceding embodiments of compounds of Formula (I), thecarbon to which R⁵ is bonded is of the S configuration.

In certain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-diethoxyethyl, phenyl, cyclohexyl, 2-pyridyl, 3-pyridyl, and4-pyridyl, R² is selected from methyl, methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, and cyclohexyloxycarbonyl, R³ is methyl, R⁵ ishydroxy, and each of R⁴, R⁶, and R⁷ is hydrogen. In certain of theimmediately preceding embodiments of compounds of Formula (I), thecarbon to which R⁵ is bonded is of the R configuration. In certain ofthe immediately preceding embodiments of compounds of Formula (I), thecarbon to which R⁵ is bonded is of the S configuration.

In certain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² is hydrogen, R³ ishydrogen, R⁵ is hydroxy, and each of R⁴, R⁶, and R⁷ is hydrogen. Incertain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² is methyl, R³ ishydrogen, R⁵ is hydroxy, and each of R⁴, R⁶, and R⁷ is hydrogen. Incertain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² is selected fromn-propyl, R³ is hydrogen, R⁵ is hydroxy, and each of R⁴, R⁶, and R⁷ ishydrogen. In certain embodiments of compounds of Formula (I), R¹ isselected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² isisopropyl, R³ is hydrogen, R⁵ is hydroxy, and each of R⁴, R⁶, and R⁷ ishydrogen. In certain of the immediately preceding embodiments ofcompounds of Formula (I), the carbon to which R⁵ is bonded is of the Rconfiguration. In certain of the immediately preceding embodiments ofcompounds of Formula (I), the carbon to which R⁵ is bonded is of the Sconfiguration.

In certain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-diethoxyethyl, phenyl, cyclohexyl, 2-pyridyl, 3-pyridyl, and4-pyridyl, R² is selected from hydrogen, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, phenyl, and cyclohexyl, R³ ishydrogen, R⁵ is fluoro, and each of R⁴, R⁶, and R⁷ is hydrogen. Incertain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-diethoxyethyl, phenyl, cyclohexyl, 2-pyridyl, 3-pyridyl, and4-pyridyl, R² is selected from hydrogen, methyl, n-propyl, andisopropyl, R³ is hydrogen, R⁵ is fluoro, and each of R⁴, R⁶, and R⁷ ishydrogen. In certain embodiments of compounds of Formula (I), R¹ isselected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² is selectedfrom hydrogen, methyl, n-propyl, and isopropyl, R³ is hydrogen, R⁵ isfluoro, and each of R⁴, R⁶, and R⁷ is hydrogen. In certain of theimmediately preceding embodiments of compounds of Formula (I), thecarbon to which R⁵ is bonded is of the R configuration. In certain ofthe immediately preceding embodiments of compounds of Formula (I), thecarbon to which R⁵ is bonded is of the S configuration.

In certain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-diethoxyethyl, phenyl, cyclohexyl, 2-pyridyl, 3-pyridyl, and4-pyridyl, R² is selected from methyl, methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, and cyclohexyloxycarbonyl, R³ is methyl, R⁵ isfluoro, and each of R⁴, R⁶, and R⁷ is hydrogen. In certain of theimmediately preceding embodiments of compounds of Formula (I), thecarbon to which R⁵ is bonded is of the R configuration. In other of theimmediately preceding embodiments of compounds of Formula (I), thecarbon to which R⁵ is bonded is of the S configuration.

In certain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² is hydrogen, R³ ishydrogen, R⁵ is fluoro, and each of R⁴, R⁶, and R⁷ is hydrogen. Incertain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² is methyl, R³ ishydrogen, R⁵ is fluoro, and each of R⁴, R⁶, and R⁷ is hydrogen. Incertain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² is n-propyl, R³ ishydrogen, R⁵ is fluoro, and each of R⁴, R⁶, and R⁷ is hydrogen. Incertain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² is isopropyl, R³ ishydrogen, R⁵ is fluoro, and each of R⁴, R⁶, and R⁷ is hydrogen. Incertain of the immediately preceding embodiments of compounds of Formula(I), the carbon to which R⁵ is bonded is of the R configuration. Incertain of the immediately preceding embodiments of compounds of Formula(I), the carbon to which R⁵ is bonded is of the S configuration.

In certain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-diethoxyethyl, phenyl, cyclohexyl, 2-pyridyl, 3-pyridyl, and4-pyridyl, R² is selected from hydrogen, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, phenyl, and cyclohexyl, R³ ishydrogen, R⁵ is oxo, and each of R⁴, R⁶, and R⁷ is hydrogen. In certainembodiments of compounds of Formula (I), R¹ is selected from methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-diethoxyethyl, phenyl,cyclohexyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl, R² is selected fromhydrogen, methyl, n-propyl, and isopropyl, R³ is hydrogen, R⁵ is oxo,and each of R⁴, R⁶, and R⁷ is hydrogen. In certain embodiments ofcompounds of Formula (I), R¹ is selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, cyclohexyl,and 3-pyridyl, R² is selected from hydrogen, methyl, n-propyl, andisopropyl, R³ is hydrogen, R⁵ is oxo, and each of R⁴, R⁶, and R⁷ ishydrogen.

In certain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-diethoxyethyl, phenyl, cyclohexyl, 2-pyridyl, 3-pyridyl, and4-pyridyl, R² is selected from methyl, methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, and cyclohexyloxycarbonyl, R³ is methyl, R⁵ is oxo,and each of R⁴, R⁶, and R⁷ is hydrogen.

In certain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² is hydrogen, R³ ishydrogen, R⁵ is oxo, and each of R⁴, R⁶, and R⁷ is hydrogen. In certainembodiments of compounds of Formula (I), R¹ is selected from methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,phenyl, cyclohexyl, and 3-pyridyl, R² is methyl, R³ is hydrogen, R⁵ isoxo, and each of R⁴, R⁶, and R⁷ is hydrogen. In certain embodiments ofcompounds of Formula (I), R¹ is selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, cyclohexyl,and 3-pyridyl, R² is n-propyl, R³ is hydrogen, R⁵ is oxo, and each ofR⁴, R⁶, and R⁷ is hydrogen. In certain embodiments of compounds ofFormula (I), R¹ is selected from methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, cyclohexyl, and3-pyridyl, R² is isopropyl, R³ is hydrogen, R⁵ is oxo, and each of R⁴,R⁶, and R⁷ is hydrogen.

In certain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-diethoxyethyl, phenyl, cyclohexyl, 2-pyridyl, 3-pyridyl, and4-pyridyl, R² is selected from hydrogen, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, phenyl, and cyclohexyl, R³ ishydrogen, R⁵ is 4-chlorophenyl, and each of R⁴, R⁶, and R⁷ is hydrogen.In certain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-diethoxyethyl, phenyl, cyclohexyl, 2-pyridyl, 3-pyridyl, and4-pyridyl, R² is selected from hydrogen, methyl, n-propyl, andisopropyl, R³ is hydrogen, R⁵ is 4-chlorophenyl, and each of R⁴, R⁶, andR⁷ is hydrogen. In certain embodiments of compounds of Formula (I), R¹is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² is selectedfrom hydrogen, methyl, n-propyl, and isopropyl, R³ is hydrogen, R⁵ is4-chlorophenyl, and each of R⁴, R⁶, and R⁷ is hydrogen. In certain ofthe immediately preceding embodiments of compounds of Formula (I), thecarbon to which R⁵ is bonded is of the R configuration. In certain ofthe immediately preceding embodiments of compounds of Formula (I), thecarbon to which R⁵ is bonded is of the S configuration.

In certain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-diethoxyethyl, phenyl, cyclohexyl, 2-pyridyl, 3-pyridyl, and4-pyridyl, R² is selected from methyl, methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, and cyclohexyloxycarbonyl, R³ is methyl, R⁵ is4-chlorophenyl, and each of R⁴, R⁶, and R⁷ is hydrogen. In certain ofthe immediately preceding embodiments of compounds of Formula (I), thecarbon to which R⁵ is bonded is of the R configuration. In certain ofthe immediately preceding embodiments of compounds of Formula (I), thecarbon to which R⁵ is bonded is of the S configuration.

In certain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² is hydrogen, R³ ishydrogen, R⁵ is 4 chlorophenyl, and each of R⁴, R⁶, and R⁷ is hydrogen.In certain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² is methyl, R³ ishydrogen, R⁵ is 4-chlorophenyl, and each of R⁴, R⁶, and R⁷ is hydrogen.In certain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² is n-propyl, R³ ishydrogen, R⁵ is 4-chlorophenyl, and each of R⁴, R⁶, and R⁷ is hydrogen.In certain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² is isopropyl, R³ ishydrogen, R⁵ is 4-chlorophenyl, and each of R⁴, R⁶, and R⁷ is hydrogen.In certain of the immediately preceding embodiments of compounds ofFormula (I), the carbon to which R⁵ is bonded is of the R configuration.In certain of the immediately preceding embodiments of compounds ofFormula (I), the carbon to which R⁵ is bonded is of the S configuration.

In certain embodiments of compounds of Formula (I), R² and R³ aredifferent and the compound of Formula (I) is substantially onediastereomer. In certain embodiments of compounds of Formula (I), thestereochemistry at the carbon to which R² and R³ are bonded is of theS-configuration and the compound of Formula (I) is substantially onediastereomer. In certain embodiments of compounds of Formula (I), thestereochemistry at the carbon to which R² and R³ are bonded is of theR-configuration, and the compound of Formula (I) is substantially onediastereomer. In certain embodiments of compounds of Formula (I), R² isC₁₋₄ alkyl, R³ is hydrogen and the compound of Formula (I) issubstantially one diastereomer. In certain embodiments of compounds ofFormula (I), R² is C₁₋₄ alkyl, R³ is hydrogen, the stereochemistry atthe carbon to which R² and R³ are bonded is of the S-configuration andthe compound of Formula (I) is substantially one diastereomer. Incertain embodiments of compounds of Formula (I), R² is C₁₋₄ alkyl, R³ ishydrogen, the stereochemistry at the carbon to which R² and R³ arebonded is of the R-configuration, and the compound of Formula (I) issubstantially one diastereomer.

In certain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² is methyl, R³ ishydrogen, R⁵ is hydroxy, each of R⁴, R⁶, and R⁷ is hydrogen, thestereochemistry at the carbon to which R² and R³ are bonded is of theS-configuration, the stereochemistry at the carbon to which R⁵ is bondedis of the R-configuration, and the compound of Formula (I) issubstantially one diastereomer. In certain embodiments of compounds ofFormula (I), R¹ is selected from methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, cyclohexyl, and3-pyridyl, R² is methyl, R³ is hydrogen, R⁵ is hydroxy, each of R⁴, R⁶,and R⁷ is hydrogen, the stereochemistry at the carbon to which R² and R³are bonded is of the R-configuration, the stereochemistry at the carbonto which R⁵ is bonded is of the R-configuration, and the compound ofFormula (a) is substantially one diastereomer. In certain embodiments ofcompounds of Formula (I), R¹ is selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, cyclohexyl,and 3-pyridyl, R² is methyl, R³ is hydrogen, R⁵ is hydroxy, each of R⁴,R⁶, and R⁷ is hydrogen, the stereochemistry at the carbon to which R²and R³ are bonded is of the S-configuration, the stereochemistry at thecarbon to which R⁵ is bonded is of the S-configuration, and the compoundof Formula (I) is substantially one diastereomer. In certain embodimentsof compounds of Formula (I), R¹ is selected from methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl,cyclohexyl, and 3-pyridyl, R² is methyl, R³ is hydrogen, R⁵ is hydroxy,each of R⁴, R⁶, and R⁷ is hydrogen, the stereochemistry at the carbon towhich R² and R³ are bonded is of the R-configuration, thestereochemistry at the carbon to which R⁵ is bonded is of theS-configuration, and the compound of Formula (I) is substantially onediastereomer. In certain embodiments of compounds of Formula (I), R¹ isselected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² isn-propyl, R³ is hydrogen, R⁵ is hydroxy, each of R⁴, R⁶, and R⁷ ishydrogen, the stereochemistry at the carbon to which R² and R³ arebonded is of the S-configuration, the stereochemistry at the carbon towhich R⁵ is bonded is of the R-configuration, and the compound ofFormula (I) is substantially one diastereomer. In certain embodiments ofcompounds of Formula (I), R¹ is selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, cyclohexyl,and 3-pyridyl, R² is n-propyl, R³ is hydrogen, R⁵ is hydroxy, each ofR⁴, R⁶, and R⁷ is hydrogen, the stereochemistry at the carbon to whichR² and R³ are bonded is of the R-configuration, the stereochemistry atthe carbon to which R⁵ is bonded is of the R-configuration, and thecompound of Formula (I) is substantially one diastereomer. In certainembodiments of compounds of Formula (I), R¹ is selected from methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,phenyl, cyclohexyl, and 3-pyridyl, R² is n-propyl, R³ is hydrogen, R⁵ ishydroxy, each of R⁴, R⁶, and R⁷ is hydrogen, the stereochemistry at thecarbon to which R² and R³ are bonded is of the S-configuration, thestereochemistry at the carbon to which R⁵ is bonded is of theS-configuration, and the compound of Formula (I) is substantially onediastereomer. In still other embodiments of compounds of Formula (I), R¹is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² isn-propyl, R³ is hydrogen, R⁵ is hydroxy, each of R⁴, R⁶, and R⁷ ishydrogen, the stereochemistry at the carbon to which R² and R³ arebonded is of the Reconfiguration, the stereochemistry at the carbon towhich R⁵ is bonded is of the S-configuration, and the compound ofFormula (I) is substantially one diastereomer. In certain embodiments ofcompounds of Formula (I), R¹ is selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, cyclohexyl,and 3-pyridyl, R² is isopropyl, R³ is hydrogen, R⁵ is hydroxy, each ofR⁴, R⁶, and R⁷ is hydrogen, the stereochemistry at the carbon to whichR² and R³ are bonded is of the S-configuration, the stereochemistry atthe carbon to which R⁵ is bonded is of the R-configuration, and thecompound of Formula (I) is substantially one diastereomer. In certainembodiments of compounds of Formula (I), R¹ is selected from methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,phenyl, cyclohexyl, and 3-pyridyl, R² is isopropyl, R³ is hydrogen, R⁵is hydroxy, each of R⁴, R⁶, and R⁷ is hydrogen, the stereochemistry atthe carbon to which R² and R³ are bonded is of the R-configuration, thestereochemistry at the carbon to which R⁵ is bonded is of theR-configuration, and the compound of Formula (I) is substantially onediastereomer. In certain embodiments of compounds of Formula (I), R¹ isselected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² isisopropyl, R³ is hydrogen, R⁵ is hydroxy, each of R⁴, R⁶, and 17 ishydrogen, the stereochemistry at the carbon to which R² and R³ arebonded is of the S-configuration, the stereochemistry at the carbon towhich R⁵ is bonded is of the S-configuration, and the compound ofFormula (I) is substantially one diastereomer. In certain embodiments ofcompounds of Formula (I), R¹ is selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, cyclohexyl,and 3-pyridyl, R² is isopropyl, R³ is hydrogen, R⁵ is hydroxy, each ofR⁴, R⁶, and R⁷ is hydrogen, the stereochemistry at the carbon to whichR² and R³ are bonded is of the R-configuration, the stereochemistry atthe carbon to which R⁵ is bonded is of the S-configuration, and thecompound of Formula (I) is substantially one diastereomer. In certainembodiments of compounds of Formula (I), R¹ is isopropyl, R² isisopropyl, R³ is hydrogen, R⁵ is hydroxy, each of R⁴, R⁶, and R⁷ ishydrogen, the stereochemistry at the carbon to which R² and R³ arebonded is of the S-configuration, the stereochemistry at the carbon towhich R⁵ is bonded is of the R-configuration, and the compound ofFormula (I) is substantially one diastereomer. In certain embodiments ofcompounds of Formula (I), R¹ is isopropyl, R² is isopropyl, R³ ishydrogen, R⁵ is hydroxy, each of R⁴, R⁶, and R⁷ is hydrogen, thestereochemistry at the carbon to which R² and R³ are bonded is of theR-configuration, the stereochemistry at the carbon to which R⁵ is bondedis of the R-configuration, and the compound of Formula (I) issubstantially one diastereomer. In certain embodiments of compounds ofFormula (I), R¹ is isopropyl, R² is isopropyl, R³ is hydrogen, R⁵ ishydroxy, each of R⁴, R⁶, and R⁷ is hydrogen, the stereochemistry at thecarbon to which R² and R³ are bonded is of the S-configuration, thestereochemistry at the carbon to which R⁵ is bonded is of theS-configuration, and the compound of Formula (I) is substantially onediastereomer. In certain embodiments of compounds of Formula (I), R¹ isisopropyl, R² is isopropyl, R³ is hydrogen, R⁵ is hydroxy, each of R⁴,R⁶, and R⁷ is hydrogen, the stereochemistry at the carbon to which R²and R³ are bonded is of the R-configuration, the stereochemistry at thecarbon to which R⁵ is bonded is of the S-configuration, and the compoundof Formula (I) is substantially one diastereomer.

In certain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² is methyl, R³ ishydrogen, R⁵ is fluoro, each of R⁴, R⁶, and R⁷ is hydrogen, thestereochemistry at the carbon to which R² and R³ are bonded is of theS-configuration, the stereochemistry at the carbon to which R⁵ is bondedis of the R-configuration, and the compound of Formula (I) issubstantially one diastereomer. In certain embodiments of compounds ofFormula (I), R¹ is selected from methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, cyclohexyl, and3-pyridyl, R² is methyl, R³ is hydrogen, R⁵ is fluoro, each of R⁴, R⁶,and R⁷ is hydrogen, the stereochemistry at the carbon to which R¹ and R³are bonded is of the R-configuration, the stereochemistry at the carbonto which R⁵ is bonded is of the R-configuration, and the compound ofFormula (I) is substantially one diastereomer. In certain embodiments ofcompounds of Formula (I), R¹ is selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, cyclohexyl,and 3-pyridyl, R² is methyl, R³ is hydrogen, R⁵ is fluoro, each of R⁴,R⁶, and R⁷ is hydrogen, the stereochemistry at the carbon to which R²and R³ are bonded is of the S-configuration, the stereochemistry at thecarbon to which R⁵ is bonded is of the S-configuration, and the compoundof Formula (I) is substantially one diastereomer. In certain embodimentsof compounds of Formula (I), R¹ is selected from methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl,cyclohexyl, and 3-pyridyl, R² is methyl, R³ is hydrogen, R⁵ is fluoro,each of R⁴, R⁶, and R⁷ is hydrogen, the stereochemistry at the carbon towhich R² and R³ are bonded is of the R-configuration, thestereochemistry at the carbon to which R⁵ is bonded is of theS-configuration, and the compound of Formula (I) is substantially onediastereomer. In certain embodiments of compounds of Formula (I), R¹ isselected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² isn-propyl, R³ is hydrogen, R⁵ is fluoro, each of R⁴, R⁶, and R⁷ ishydrogen, the stereochemistry at the carbon to which R² and R³ arebonded is of the S-configuration, the stereochemistry at the carbon towhich R⁵ is bonded is of the R-configuration, and the compound ofFormula (I) is substantially one diastereomer. In certain embodiments ofcompounds of Formula (I), R¹ is selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, cyclohexyl,and 3-pyridyl, R² is n-propyl, R³ is hydrogen, R⁵ is fluoro, each of R⁴,R⁶, and R⁷ is hydrogen, the stereochemistry at the carbon to which R²and R³ are bonded is of the R-configuration, the stereochemistry at thecarbon to which R⁵ is bonded is of the R-configuration, and the compoundof Formula (I) is substantially one diastereomer. In certain embodimentsof compounds of Formula (I), R¹ is selected from methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl,cyclohexyl, and 3-pyridyl, R² is n-propyl, R³ is hydrogen, R⁵ is fluoro,each of R⁴, R⁶, and R⁷ is hydrogen, the stereochemistry at the carbon towhich R² and R³ are bonded is of the S-configuration, thestereochemistry at the carbon to which R⁵ is bonded is of theS-configuration, and the compound of Formula (I) is substantially onediastereomer. In certain embodiments of compounds of Formula (I), R¹ isselected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² isn-propyl, R³ is hydrogen, R⁵ is fluoro, each of R⁴, R⁶, and R⁷ ishydrogen, the stereochemistry at the carbon to which R² and R³ arebonded is of the R-configuration, the stereochemistry at the carbon towhich R⁵ is bonded is of the S-configuration, and the compound ofFormula (I) is substantially one diastereomer. In certain embodiments ofcompounds of Formula (I), R¹ is selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, cyclohexyl,and 3-pyridyl, R² is isopropyl, R³ is hydrogen, R⁵ is fluoro, each ofR⁴, R⁶, and R⁷ is hydrogen, the stereochemistry at the carbon to whichR² and R³ are bonded is of the S-configuration, the stereochemistry atthe carbon to which R⁵ is bonded is of the R-configuration, and thecompound of Formula (I) is substantially one diastereomer. In certainembodiments of compounds of Formula (I), R¹ is selected from methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,phenyl, cyclohexyl, and 3-pyridyl, R² is isopropyl, R³ is hydrogen, R⁵is fluoro, each of R⁴, R⁶, and R⁷ is hydrogen, the stereochemistry atthe carbon to which R² and R³ are bonded is of the R-configuration, thestereochemistry at the carbon to which R⁵ is bonded is of theR-configuration, and the compound of Formula (I) is substantially onediastereomer. In certain embodiments of compounds of Formula (I), R¹ isselected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² isisopropyl, R³ is hydrogen, R⁵ is fluoro, each of R⁴, R⁶, and R⁷ ishydrogen, the stereochemistry at the carbon to which R² and R³ arebonded is of the S-configuration, the stereochemistry at the carbon towhich R⁵ is bonded is of the S-configuration, and the compound ofFormula (I) is substantially one diastereomer. In certain embodiments ofcompounds of Formula (I), R¹ is selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, cyclohexyl,and 3-pyridyl, R² is isopropyl, R³ is hydrogen, R⁵ is fluoro, each ofR⁴, R⁶, and R⁷ is hydrogen, the stereochemistry at the carbon to whichR² and R³ are bonded is of the R-configuration, the stereochemistry atthe carbon to which R⁵ is bonded is of the S-configuration, and thecompound of Formula (I) is substantially one diastereomer. In certainembodiments of compounds of Formula (I), R¹ is isopropyl, R² isisopropyl, R³ is hydrogen, R⁵ is fluoro, each of R⁴, R⁶, and R⁷ ishydrogen, the stereochemistry at the carbon to which R² and R³ arebonded is of the S-configuration, the stereochemistry at the carbon towhich R⁵ is bonded is of the R-configuration, and the compound ofFormula (I) is substantially one diastereomer. In certain embodiments ofcompounds of Formula (I), R¹ is isopropyl, R² is isopropyl, R³ ishydrogen, R⁵ is fluoro, each of R⁴, R⁶, and R⁷ is hydrogen, thestereochemistry at the carbon to which R² and R³ are bonded is of theR-configuration, the stereochemistry at the carbon to which R⁵ is bondedis of the R-configuration, and the compound of Formula (I) issubstantially one diastereomer. In certain embodiments of compounds ofFormula (I), R¹ is isopropyl, R² is isopropyl, R³ is hydrogen, R⁵ isfluoro, each of R⁴, R⁶, and R⁷ is hydrogen, the stereochemistry at thecarbon to which R² and R³ are bonded is of the S-configuration, thestereochemistry at the carbon to which R⁵ is bonded is of theS-configuration, and the compound of Formula (I) is substantially onediastereomer. In certain embodiments of compounds of Formula (I), R¹ isisopropyl, R² is isopropyl, R³ is hydrogen, R⁵ is fluoro, each of R⁴,R⁶, and R⁷ is hydrogen, the stereochemistry at the carbon to which R²and R³ are bonded is of the R-configuration, the stereochemistry at thecarbon to which R⁵ is bonded is of the S-configuration, and the compoundof Formula (I) is substantially one diastereomer.

In certain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² is methyl, R³ ishydrogen, R⁵ is 4-chlorophenyl, each of R⁴, R⁶, and R⁷ is hydrogen, thestereochemistry at the carbon to which R² and R³ are bonded is of theS-configuration, the stereochemistry at the carbon to which R⁵ is bondedis of the R-configuration, and the compound of Formula (I) issubstantially one diastereomer. In certain embodiments of compounds ofFormula (I), R¹ is selected from methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, cyclohexyl, and3-pyridyl, R² is methyl, R³ is hydrogen, R⁵ is 4-chlorophenyl, each ofR⁴, R⁶, and R⁷ is hydrogen, the stereochemistry at the carbon to whichR² and R³ are bonded is of the R-configuration, the stereochemistry atthe carbon to which R⁵ is bonded is of the R-configuration, and thecompound of Formula (I) is substantially one diastereomer. In certainembodiments of compounds of Formula (I), R¹ is selected from methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,phenyl, cyclohexyl, and 3-pyridyl, R² is methyl, R³ is hydrogen, R⁵ is4-chlorophenyl, each of R⁴, R⁶, and R⁷ is hydrogen, the stereochemistryat the carbon to which R² and R³ are bonded is of the S-configuration,the stereochemistry at the carbon to which R⁵ is bonded is of theS-configuration, and the compound of Formula (I) is substantially onediastereomer. In certain embodiments of compounds of Formula (I), R¹ isselected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² is methyl,R³ is hydrogen, R⁵ is 4-chlorophenyl, each of R⁴, R⁶, and R⁷ ishydrogen, the stereochemistry at the carbon to which R² and R³ arebonded is of the R-configuration, the stereochemistry at the carbon towhich R⁵ is bonded is of the S-configuration, and the compound ofFormula (I) is substantially one diastereomer. In certain embodiments ofcompounds of Formula (I), R¹ is selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, cyclohexyl,and 3-pyridyl, R² is n-propyl, R³ is hydrogen, R⁵ is 4-chlorophenyl,each of R⁴, R⁶, and R⁷ is hydrogen, the stereochemistry at the carbon towhich R² and R³ are bonded is of the S-configuration, thestereochemistry at the carbon to which R⁵ is bonded is of theR-configuration, and the compound of Formula (I) is substantially onediastereomer. In certain embodiments of compounds of Formula (I), R¹ isselected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² isn-propyl, R³ is hydrogen, R⁵ is 4-chlorophenyl, each of R⁴, R⁶, and R⁷is hydrogen, the stereochemistry at the carbon to which R² and R³ arebonded is of the R-configuration, the stereochemistry at the carbon towhich R⁵ is bonded is of the R-configuration, and the compound ofFormula (I) is substantially one diastereomer. In certain embodiments ofcompounds of Formula (I), R¹ is selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, cyclohexyl,and 3-pyridyl, R² is n-propyl, R³ is hydrogen, R⁵ is 4-chlorophenyl,each of R⁴, R⁶, and R⁷ is hydrogen, the stereochemistry at the carbon towhich R² and R³ are bonded is of the S-configuration, thestereochemistry at the carbon to which R⁵ is bonded is of theS-configuration, and the compound of Formula (I) is substantially onediastereomer. In certain embodiments of compounds of Formula (I), R¹ isselected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² isn-propyl, R³ is hydrogen, R⁵ is 4-chlorophenyl, each of R⁴, R⁶, and R⁷is hydrogen, the stereochemistry at the carbon to which R² and R³ arebonded is of the R-configuration, the stereochemistry at the carbon towhich R⁵ is bonded is of the S-configuration, and the compound ofFormula (I) is substantially one diastereomer. In certain embodiments ofcompounds of Formula (I), R¹ is selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, cyclohexyl,and 3-pyridyl, R² is isopropyl, R³ is hydrogen, R⁵ is 4-chlorophenyl,each of R⁴, R⁶, and R⁷ is hydrogen, the stereochemistry at the carbon towhich R² and R³ are bonded is of the S-configuration, thestereochemistry at the carbon to which R⁵ is bonded is of theR-configuration, and the compound of Formula (I) is substantially onediastereomer. In certain embodiments of compounds of Formula (I), R¹ isselected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² isisopropyl, R³ is hydrogen, R⁵ is 4-chlorophenyl, each of R⁴, R⁶, and R⁷is hydrogen, the stereochemistry at the carbon to which R² and R³ arebonded is of the R-configuration, the stereochemistry at the carbon towhich R⁵ is bonded is of the R-configuration, and the compound ofFormula (I) is substantially one diastereomer. In certain embodiments ofcompounds of Formula (I), R¹ is selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, cyclohexyl,and 3-pyridyl, R² is isopropyl, R³ is hydrogen, R⁵ is 4-chlorophenyl,each of R⁴, R⁶, and R⁷ is hydrogen, the stereochemistry at the carbon towhich R² and R³ are bonded is of the S-configuration, thestereochemistry at the carbon to which R⁵ is bonded is of theS-configuration, and the compound of Formula (I) is substantially onediastereomer. In certain embodiments of compounds of Formula (I), R¹ isselected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² isisopropyl, R³ is hydrogen, R⁵ is 4-chlorophenyl, each of R⁴, R⁶, and R⁷is hydrogen, the stereochemistry at the carbon to which R² and R³ arebonded is of the R-configuration, the stereochemistry at the carbon towhich R⁵ is bonded is of the S-configuration, and the compound ofFormula (I) is substantially one diastereomer. In certain embodiments ofcompounds of Formula (I), R¹ is isopropyl, R² is isopropyl, R³ ishydrogen, R⁵ is 4-chlorophenyl, each of R⁴, R⁶, and R⁷ is hydrogen, thestereochemistry at the carbon to which R² and R³ are bonded is of theS-configuration, the stereochemistry at the carbon to which R⁵ is bondedis of the R-configuration, and the compound of Formula (I) issubstantially one diastereomer. In certain embodiments of compounds ofFormula (I), R¹ is isopropyl, R² is isopropyl, R³ is hydrogen, R⁵ is4-chlorophenyl, each of R⁴, R⁶, and R⁷ is hydrogen, the stereochemistryat the carbon to which R² and R³ are bonded is of the R-configuration,the stereochemistry at the carbon to which R⁵ is bonded is of theR-configuration, and the compound of Formula (I) is substantially onediastereomer. In certain embodiments of compounds of Formula (I), R¹ isisopropyl, R² is isopropyl, R³ is hydrogen, R⁵ is 4-chlorophenyl, eachof R⁴, R⁶, and R⁷ is hydrogen, the stereochemistry at the carbon towhich R² and R³ are bonded is of the S-configuration, thestereochemistry at the carbon to which R⁵ is bonded is of theS-configuration, and the compound of Formula (I) is substantially onediastereomer. In certain embodiments of compounds of Formula (I), R¹ isisopropyl, R² is isopropyl, R³ is hydrogen, R⁵ is 4-chlorophenyl, eachof R⁴, R⁶, and R⁷ is hydrogen, the stereochemistry at the carbon towhich R² and R³ are bonded is of the R-configuration, thestereochemistry at the carbon to which R⁵ is bonded is of theS-configuration, and the compound of Formula (I) is substantially onediastereomer.

In certain embodiments of compounds of Formula (I), R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, cyclohexyl, and 3-pyridyl, R² is selected fromhydrogen, methyl, n-propyl, and isopropyl, R³ is hydrogen, R⁵ isselected from hydrogen, hydroxy, fluoro, oxo, and 4-chlorophenyl, andeach of R⁴, R⁶, and R⁷ are hydrogen.

In certain embodiments of compounds of Formula (I), R¹ is isopropyl, R²is isopropyl, R³ is hydrogen, R⁵ is selected from hydrogen, hydroxy,fluoro, oxo, and 4-chlorophenyl, and each of R⁴, R⁶, and R⁷ arehydrogen.

Synthesis

The compounds disclosed herein may be obtained via the synthetic methodillustrated in Scheme 1. Those of ordinary skill in the art willappreciate that a synthetic route to the disclosed compounds consists ofattaching promoieties to 3-aminopropylsulfinic acid analogs. Numerousmethods have been described in the art for the synthesis of3-aminopropylsulfinic acid analogs (e.g., Carruthers et al., Bioorg.Med. Chem. Lett. 1995, 5, 237-240; Shue et al., Bioorg. Med. Chem. Lett.1996, 6, 1709-1714; Carruthers et al., Bioorg. Med. Chem. Lett. 1998, 8,3059-3064; and Fitzpatrick et al., International Publication No. WO02/100823, each of which is incorporated herein by reference in itsentirety). General synthetic methods useful in the synthesis of thecompounds described herein are also available in the art (e.g., Green etal., “Protective Groups in Organic Chemistry,” Wiley, 2^(nd) ed. 1991;Harrison et al., “Compendium of Synthetic Organic Methods,” Vols. 1-8(John Wiley and Sons, 1971-1996; Larock “Comprehensive OrganicTransformations,” VCH Publishers, 1989; and Paquette, “Encyclopedia ofReagents for Organic Synthesis,” John Wiley & Sons, 1995).

Accordingly, starting materials useful for preparing compounds andintermediates thereof, and/or practicing methods described herein arecommercially available or can be prepared by well-known syntheticmethods. Other methods for synthesis of the prodrugs described hereinare either described in the art or will be readily apparent to theskilled artisan in view of the references provided herein and may beused to synthesize the compounds described herein. Accordingly, themethods presented in the Schemes of the present disclosure areillustrative rather than comprehensive.

A method for synthesizing compounds of Formula (I), illustrated inScheme 1, employs the reaction of a 3-aminopropylsulfinic acid analog ofFormula (II) with a 1-(acyloxy)-alkyl N-hydroxysuccinimidyl carbonatecompound of Formula (III), optionally in the presence of a base, asdescribed in the co-pending application Gallop et al., InternationalPublication No. WO 2005/010011, which is incorporated herein byreference in its entirety.

wherein:

R⁹ and R¹⁰ are independently selected from hydrogen, acylamino, acyloxy,alkoxycarbonylamino, alkoxycarbonyloxy, alkyl, substituted alkyl,alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl,carbamoyloxy, dialkylamino, heteroaryl, hydroxy, and sulfonamido, or, R⁹and R¹⁰ together with the atoms to which they are bonded form asubstituted cycloalkyl, substituted cycloheteroalkyl, or substitutedaryl ring; and

R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are as defined herein.

In certain embodiments of the method of Scheme 1 for synthesizing acompound of Formula (I), R² and R³ in the compound of Formula (III) aredifferent, such that the carbon atom to which these substituents arebonded is a stereogenic center.

In certain embodiments of the method of Scheme 1 for synthesizing acompound of Formula (I), each of R⁹ and R¹⁰ in the compound of Formula(III) is benzoyloxy, the stereochemistry at the carbon to which R⁹ isbonded is of the R-configuration, and the stereochemistry at the carbonto which R¹⁰ is bonded is of the R-configuration. In certain embodimentsof the method of Scheme 1 for synthesizing a compound of Formula (I),each of R⁹ and R¹⁰ in the compound of Formula (III) is benzoyloxy, thestereochemistry at the carbon to which R⁹ is bonded is of theS-configuration, and the stereochemistry at the carbon to which R¹⁰ isbonded is of the S-configuration.

In certain embodiments of the method of Scheme 1 for synthesizing acompound of Formula (I), R² and R³ in the compound of Formula (I) aredifferent and the compound of Formula (I) is substantially onediastereomer. In certain embodiments of the method of Scheme 1 forsynthesizing a compound of Formula (I), R¹ is isopropyl, R² isisopropyl, R³ is hydrogen, the stereochemistry at the carbon to which R²and R³ are bonded is of the S-configuration and the compound of Formula(I) is substantially one diastereomer. In certain embodiments of themethod of Scheme 1 for synthesizing a compound of Formula (I), R¹ isisopropyl, R² is isopropyl, R³ is hydrogen, the stereochemistry at thecarbon to which R² and R³ are bonded is of the R-configuration, and thecompound of Formula (I) is substantially one diastereomer.

In certain embodiments of the method of Scheme 1 for synthesizing acompound of Formula (I), R¹ is C₁₋₆ alkyl, R² is hydrogen or C₁₋₄ alkyl,R³ is hydrogen, R⁵ is selected from hydroxy, fluoro, and 4-chlorophenyl,each of R⁴, R⁶, and R⁷ is hydrogen, each of R⁹ and R¹⁰ is benzoyloxy,and the stereochemistry at the carbon to which R¹ is bonded is of theR-configuration. In certain embodiments of the method of Scheme 1 forsynthesizing a compound of Formula (I), R¹ is C₁₋₄ alkyl, R² is hydrogenor C₁₋₄ alkyl, R³ is hydrogen, R⁵ is selected from hydroxy, fluoro, and4-chlorophenyl, each of R⁴, R⁶, and R⁷ is hydrogen, each of R⁹ and R¹⁰is benzoyloxy, and the stereochemistry at the carbon to which R⁵ isbonded is of the S-configuration. In certain embodiments of the methodof Scheme 1 for synthesizing a compound of Formula (I), R¹ is C₁₋₆alkyl, R² is methyl, R³ is hydrogen, R⁵ is selected from hydroxy,fluoro, and 4-chlorophenyl, each of R⁴, R⁶, and R⁷ is hydrogen, each ofR⁹ and R¹⁰ is benzoyloxy, and the stereochemistry at the carbon to whichR⁵ is bonded is of the R-configuration. In certain embodiments of themethod of Scheme 1 for synthesizing a compound of Formula (I), R¹ isC₁₋₆ alkyl, 2 is methyl, R³ is hydrogen, R⁵ is selected from hydroxy,fluoro, and 4-chlorophenyl, each of R⁴, R⁶, and R⁷ is hydrogen, each ofR⁹ and R¹⁰ is benzoyloxy, and the stereochemistry at the carbon to whichR⁵ is bonded is of the S-configuration. In certain embodiments of themethod of Scheme 1 for synthesizing a compound of Formula (I), R¹ isC₁₋₆ alkyl, R² is propyl, R³ is hydrogen, R⁵ is selected from hydroxy,fluoro, and 4-chlorophenyl, each of R⁴, R⁶, and R⁷ is hydrogen, each ofR⁹ and R¹⁰ is benzoyloxy, and the stereochemistry at the carbon to whichR⁵ is bonded is of the R-configuration. In certain embodiments of themethod of Scheme 1 for synthesizing a compound of Formula (I), R¹ isC₁₋₆ alkyl, R² is propyl, R³ is hydrogen, R⁵ is selected from hydroxy,fluoro, and 4-chlorophenyl, each of R⁴, R⁶, and R⁷ is hydrogen, each ofR⁹ and R¹⁰ is benzoyloxy, and the stereochemistry at the carbon to whichR⁵ is bonded is of the S-configuration. In certain embodiments of themethod of Scheme 1 for synthesizing a compound of Formula (I), R¹ isC₁₋₆ alkyl, R² is isopropyl, R³ is hydrogen, R⁵ is selected fromhydroxy, fluoro, and 4-chlorophenyl, each of R⁴, R⁶, and R⁷ is hydrogen,each of R⁹ and R¹⁰ is benzoyloxy, and the stereochemistry at the carbonto which R⁵ is bonded is of the R-configuration. In certain embodimentsof the method of Scheme 1 for synthesizing a compound of Formula (I), R¹is C₁₋₆ alkyl, R² is isopropyl, R³ is hydrogen, R⁵ is selected fromhydroxy, fluoro, and 4-chlorophenyl, each of R⁴, R⁶, and R⁷ is hydrogen,each of R⁹ and R¹⁰ is benzoyloxy, and the stereochemistry at the carbonto which R⁵ is bonded is of the S-configuration.

In certain embodiments of the method of Scheme 1 for synthesizing acompound of Formula (I), R¹ is C₁₋₆ alkyl, R² is methyl, R³ is hydrogen,R⁵ is selected from hydroxy, fluoro, and 4-chlorophenyl, each of R⁴, R⁶,and R⁷ is hydrogen, each of R⁹ and R¹⁰ is benzoyloxy, thestereochemistry at the carbon to which R² and R³ are bonded is of theS-configuration, the stereochemistry at the carbon to which R⁵ is bondedis of the R-configuration, the stereochemistry at the carbon to which R⁹is bonded is of the R-configuration, and the stereochemistry at thecarbon to which R¹⁰ is bonded is of the R-configuration. In certainembodiments of the method of Scheme 1 for synthesizing a compound ofFormula (I), R¹ is C₁₋₆ alkyl, R² is methyl, R³ is hydrogen, R⁵ isselected from hydroxy, fluoro, and 4-chlorophenyl, each of R⁴, R⁶, andR⁷ is hydrogen, each of R⁹ and R¹⁰ is benzoyloxy, the stereochemistry atthe carbon to which R² and R³ are bonded is of the S-configuration, thestereochemistry at the carbon to which R⁵ is bonded is of theS-configuration, the stereochemistry at the carbon to which R⁹ is bondedis of the R-configuration, and the stereochemistry at the carbon towhich R¹⁰ is bonded is of the R-configuration. In certain embodiments ofthe method of Scheme 1 for synthesizing a compound of Formula (I), R¹ isC₁₋₆ alkyl, R² is methyl, R³ is hydrogen, R⁵ is selected from hydroxy,fluoro, and 4-chlorophenyl, each of R⁴, R⁶, and R⁷ is hydrogen, each ofR⁹ and R¹⁰ is benzoyloxy, the stereochemistry at the carbon to which R²and R³ are bonded is of the R-configuration, the stereochemistry at thecarbon to which R⁵ is bonded is of the R-configuration, thestereochemistry at the carbon to which R⁹ is bonded is of theS-configuration and the stereochemistry at the carbon to which R¹⁰ isbonded is of the S-configuration. In certain embodiments of the methodof Scheme 1 for synthesizing a compound of Formula (I), R¹ is C₁₋₆alkyl, R² is methyl, R³ is hydrogen, R⁵ is selected from hydroxy,fluoro, and 4-chlorophenyl, each of R⁴, R⁶, and R⁷ is hydrogen, each ofR⁹ and R¹⁰ is benzoyloxy, the stereochemistry at the carbon to which R²and R³ are bonded is of the R-configuration, the stereochemistry at thecarbon to which R⁵ is bonded is of the S-configuration, thestereochemistry at the carbon to which R⁹ is bonded is of theS-configuration and the stereochemistry at the carbon to which R¹⁰ isbonded is of the S-configuration. In certain embodiments of the methodof Scheme 1 for synthesizing a compound of Formula (I), R¹ is C₁₋₆alkyl, R² is propyl, R³ is hydrogen, R⁵ is selected from hydroxy,fluoro, and 4-chlorophenyl, each of R⁴, R⁶, and R⁷ is hydrogen, each ofR⁹ and R¹⁰ is benzoyloxy, the stereochemistry at the carbon to which R²and R³ are bonded is of the S-configuration, the stereochemistry at thecarbon to which R⁵ is bonded is of the R-configuration, thestereochemistry at the carbon to which R⁹ is bonded is of theR-configuration, and the stereochemistry at the carbon to which R¹⁵ isbonded is of the R-configuration. In certain embodiments of the methodof Scheme 1 for synthesizing a compound of Formula (I), R¹ is C₁₋₆alkyl, R² is propyl, R³ is hydrogen, R⁵ is selected from hydroxy,fluoro, and 4-chlorophenyl, each of R⁴, R⁶, and R⁷ is hydrogen, each ofR⁹ and R¹⁰ is benzoyloxy, the stereochemistry at the carbon to which R²and R³ are bonded is of the S-configuration, the stereochemistry at thecarbon to which R⁵ is bonded is of the S-configuration, thestereochemistry at the carbon to which R⁹ is bonded is of theR-configuration, and the stereochemistry at the carbon to which R¹⁰ isbonded is of the R-configuration. In certain embodiments of the methodof Scheme 1 for synthesizing a compound of Formula (I), R¹ is C₁₋₆alkyl, R² is propyl, R³ is hydrogen, R⁵ is selected from hydroxy,fluoro, and 4-chlorophenyl, each of R⁴, R⁶, and R⁷ is hydrogen, each ofR⁹ and R¹⁰ is benzoyloxy, the stereochemistry at the carbon to which R²and R³ are bonded is of the R-configuration, the stereochemistry at thecarbon to which R⁵ is bonded is of the R-configuration, thestereochemistry at the carbon to which R⁹ is bonded is of theS-configuration and the stereochemistry at the carbon to which R¹⁰ isbonded is of the S-configuration. In certain embodiments of the methodof Scheme 1 for synthesizing a compound of Formula (I), R¹ is C₁₋₆alkyl, R² is propyl, R³ is hydrogen, R⁵ is selected from hydroxy,fluoro, and 4-chlorophenyl, each of R⁴, R⁶, and R⁷ is y hydrogen, eachof R⁹ and R¹⁰ is benzoyloxy, the stereochemistry at the carbon to whichR² and R³ are bonded is of the R-configuration, the stereochemistry atthe carbon to which R⁵ is bonded is of the S-configuration, thestereochemistry at the carbon to which R⁹ is bonded is of theS-configuration and the stereochemistry at the carbon to which R¹⁰ isbonded is of the S-configuration. In certain embodiments of the methodof Scheme 1 for synthesizing a compound of Formula (I), R¹ is C₁₋₆alkyl, R² is isopropyl, R³ is hydrogen, R⁵ is selected from hydroxy,fluoro, and 4-chlorophenyl, each of R⁴, R⁶, and R⁷ is hydrogen, each ofR⁹ and R¹⁰ is benzoyloxy, the stereochemistry at the carbon to which R²and R³ are bonded is of the S-configuration, the stereochemistry at thecarbon to which R⁵ is bonded is of the R-configuration, thestereochemistry at the carbon to which R⁹ is bonded is of theR-configuration, and the stereochemistry at the carbon to which R¹⁰ isbonded is of the R-configuration. In certain embodiments of the methodof Scheme 1 for synthesizing a compound of Formula (I), R¹ is C₁₋₆alkyl, R² is isopropyl, R³ is hydrogen, R⁵ is selected from hydroxy,fluoro, and 4-chlorophenyl, each of R⁴, R⁶, and R⁷ is hydrogen, each ofR⁹ and R¹⁰ is benzoyloxy, the stereochemistry at the carbon to which R²and R³ are bonded is of the S-configuration, the stereochemistry at thecarbon to which R⁵ is bonded is of the S-configuration, thestereochemistry at the carbon to which R⁹ is bonded is of theR-configuration, and the stereochemistry at the carbon to which R¹⁰ isbonded is of the R-configuration. In certain embodiments of the methodof Scheme 1 for synthesizing a compound of Formula (I), R¹ is C₁₋₆alkyl, R² is isopropyl, R³ is hydrogen, R⁵ is selected from hydroxy,fluoro, and 4-chlorophenyl, each of R⁴, R⁶, and R⁷ is hydrogen, each ofR⁹ and R¹⁰ is benzoyloxy, the stereochemistry at the carbon to which R²and R³ are attached is of the R-configuration, the stereochemistry atthe carbon to which R⁵ is bonded is of the R-configuration, thestereochemistry at the carbon to which R⁹ is bonded is of theS-configuration and the stereochemistry at the carbon to which R¹⁰ isbonded is of the S-configuration. In certain embodiments of the methodof Scheme 1 for synthesizing a compound of Formula (I), R¹ is C₁₋₆alkyl, R² is isopropyl, R³ is hydrogen, R⁵ is selected from hydroxy,fluoro, and 4-chlorophenyl, each of R⁴, R⁶, and R⁷ is hydrogen, each ofR⁹ and R¹⁰ is benzoyloxy, the stereochemistry at the carbon to which R²and R³ are bonded is of the R-configuration, the stereochemistry at thecarbon to which R⁵ is bonded is of the S-configuration, thestereochemistry at the carbon to which R⁹ is bonded is of theS-configuration and the stereochemistry at the carbon to which R¹⁰ isbonded is of the S-configuration.

In certain embodiments, the method of Scheme 1 can be carried out in asolvent. Useful solvent include, but are not limited to, acetone,acetonitrile, dichloromethane, dichloroethane, chloroform, toluene,tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide,N-methylpyrrolidinone, dimethyl sulfoxide, pyridine, ethyl acetate,methyl tert-butyl ether, methanol, ethanol, isopropanol, tert-butanol,water, or combinations thereof. In certain embodiments, the solvent isacetone, acetonitrile, dichloromethane, toluene, tetrahydrofuran,pyridine, methyl tert-butyl ether, methanol, ethanol, isopropanol,water, or combinations thereof. In certain embodiments, the solvent is amixture of acetonitrile and water. In certain embodiments, the solventis a mixture of acetonitrile and water, with a volume ratio ofacetonitrile to water from about 1:5 to about 5:1. In certainembodiments, the solvent is a mixture of tetrahydrofuran and water, witha volume ratio of tetrahydrofuran to water from about 20:1 to about 2:1.In certain embodiments, the solvent is a mixture of methyl tert-butylether and water. In certain embodiments, the solvent is a mixture ofmethyl tert-butyl ether and water, with a volume ratio of methyltert-butyl ether to water from about 20:1 to about 2:1. In certainembodiments, the solvent is a mixture of methyl tert-butyl ether andwater, wherein the methyl tert-butyl ether contains from about 10% toabout 50% acetone by volume. In certain embodiments, the solvent isdichloromethane, water, or a combination thereof. In certainembodiments, the solvent is a biphasic mixture of dichloromethane andwater. In certain embodiments, the solvent is a biphasic mixture ofdichloromethane and water containing from about 0.001 equivalents toabout 0.1 equivalents of a phase transfer catalyst. In certainembodiments, the phase transfer catalyst is a tetraalkylammonium salt,and in certain embodiments, the phase transfer catalyst is atetrabutylammonium salt.

The method of Scheme 1 can be carried out a temperature from about −20°C. to about 40° C. In certain embodiments, the temperature can be fromabout −20° C. to about 25° C. In certain embodiments, the temperaturecan be from about 0° C. to about 25° C. In certain embodiments, thetemperature can be from about 25° C. to about 40° C.

In certain embodiments of the method of Scheme 1, the reaction can beperformed in the absence of a base.

In certain embodiments of the method of Scheme 1, the reaction can beperformed in the presence of an inorganic base. In certain embodiments,the reaction can be performed in the presence of an alkali metalbicarbonate or alkali metal carbonate salt. In certain embodiments, thereaction can be performed in the presence of sodium bicarbonate

In certain embodiments of the method of Scheme 1, the reaction can beperformed in the presence of an organic base. In certain embodiments,the reaction can be performed in the presence of an organic base such astriethylamine, tributylamine, diisopropylethylamine,dimethylisopropylamine, N-methylmorpholine, N-methylpyrrolidine,N-methylpiperidine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine,4-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane,1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]undec-7-ene,or a combination of any of the foregoing, and in certain embodiments,the reaction can be performed in the presence of an organic base such astriethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, or acombination of any of the foregoing.

Pharmaceutical Compositions

Pharmaceutical compositions comprising a therapeutically effectiveamount of one or more prodrugs of 3-aminopropylsulfinic acid or analogof Formula (I), such as in purified form, together with a suitableamount of a pharmaceutically acceptable vehicle, so as to provide a formfor proper administration to a patient are provided herein. Suitablepharmaceutical vehicles include excipients such as starch, glucose,lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodiumstearate, glycerol monostearate, talc, sodium chloride, dried skim milk,glycerol, propylene, glycol, water, ethanol, and the like. The presentcompositions, if desired, can also contain minor amounts of wetting oremulsifying agents, or pH buffering agents. In addition, auxiliary,stabilizing, thickening, lubricating, and coloring agents may be used.

Pharmaceutical compositions may be manufactured by means of conventionalmixing, dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping, or lyophilizing processes. Pharmaceuticalcompositions may be formulated in conventional manner using one or morephysiologically acceptable carriers, diluents, excipients, orauxiliaries, which facilitate processing of compounds disclosed hereininto preparations, which can be used pharmaceutically. Properformulation can depend upon the route of administration chosen.

The present pharmaceutical compositions can take the form of solutions,suspensions, emulsions, tablets, pills, pellets, capsules, capsulescontaining liquids, powders, sustained-release formulations,suppositories, emulsions, aerosols, sprays, suspensions, or any otherform suitable for use. In some embodiments, the pharmaceuticallyacceptable vehicle is a capsule (see e.g., Grosswald et al., U.S. Pat.No. 5,698,155). Other examples of suitable pharmaceutical vehicles havebeen described in the art (see “Remington's Pharmaceutical Sciences,”Lippincott Williams & Wilkins, 21st Edition, 2005). In some embodiments,compositions are formulated for oral delivery, particularly forsustained release oral administration.

Pharmaceutical compositions for oral delivery may be in the form oftablets, lozenges, aqueous or oily suspensions, granules, powders,emulsions, capsules, syrups, or elixirs, for example. Orallyadministered compositions may contain one or more optional agents, forexample, sweetening agents such as fructose, aspartame or saccharin,flavoring agents such as peppermint, oil of wintergreen, or cherrycoloring agents, and preserving agents, to provide a pharmaceuticallypalatable preparation. Moreover, when in tablet or pill form, acomposition may be coated to delay disintegration and absorption in thegastrointestinal tract, thereby providing a sustained action over anextended period of time. Oral compositions can include standard vehiclessuch as mannitol, lactose, starch, magnesium stearate, sodiumsaccharine, cellulose, magnesium carbonate, etc. Such vehicles aregenerally of pharmaceutical grade.

For oral liquid preparations such as, for example, suspensions, elixirsand solutions, suitable carriers, excipients, or diluents include water,saline, alkyleneglycols (e.g., propylene glycol), polyalkylene glycols(e.g., polyethylene glycol) oils, alcohols, slightly acidic buffersbetween pH 4 and pH 6 (e.g., acetate, citrate, ascorbate at betweenabout 5 mM to about 50 mM), etc. Additionally, flavoring agents,preservatives, coloring agents, bile salts, acylcarnitines, and the likemay be added.

When a compound of Formula (I) is acidic, it may be included in any ofthe above-described formulations as the free acid, a pharmaceuticallyacceptable salt, a solvate, or a hydrate. Pharmaceutically acceptablesalts substantially retain the activity of the free acid, may beprepared by reaction with bases, and tend to be more soluble in aqueousand other protic solvents than the corresponding free acid form. Incertain embodiments, sodium salts of a compound of Formula (I) are usedin the above described formulations.

Sustained Release Oral Dosage Forms

Prodrugs of 3-aminopropylsulfinic acid or analogs thereof of Formula (I)can be used with a number of different dosage forms, which may beadapted to provide sustained release of a compound of Formula (I) uponoral administration.

In some embodiments, a dosage form can comprise beads that ondissolution or diffusion release a compound of the present disclosureover an extended period of hours, in certain embodiments, over a periodof at least about 6 hours, such as, in certain embodiments over a periodof at least about 8 hours, and in certain embodiments, over a period ofat least about 12 hours. The beads may have a central composition orcore comprising a compound of the present disclosure andpharmaceutically acceptable vehicles, including an optional lubricant,antioxidant and buffer. The beads may be medical preparations with adiameter of about 0.05 mm to about 2 mm. Individual beads may comprisedoses of a compound of the present disclosure, for example, doses of upto about 40 mg of compound. The beads, in some embodiments, can beformed of non-cross-linked materials to enhance their discharge from thegastrointestinal tract. The beads may be coated with a releaserate-controlling polymer that gives a timed release profile.

The time-release beads may be manufactured into a tablet fortherapeutically effective administration. The beads can be made intomatrix tablets by the direct compression of a plurality of beads coatedwith, for example, an acrylic resin and blended with excipients such ashydroxypropylmethyl cellulose. The manufacture of beads has beendisclosed in the art (Lu, Int. J. Pharm. 1994, 112, 117-124;“Remington's Pharmaceutical Sciences”, Lippincott Williams & Wikins,21st Edition, 2005; Fincher, J. Pharm. Sci. 1968, 57, 1825-1835; andU.S. Pat. No. 4,083,949), as has the manufacture of tablets(“Remington's Pharmaceutical Sciences”, Lippincott Williams & Wilkins,21st Edition, 2005).

One type of sustained release oral dosage formulation that may be usedwith compounds of the present disclosure can comprise an inert core,such as a sugar sphere, coated with an inner drug-containing layer andan outer membrane layer controlling drug release from the inner layer. A“sealcoat” may be provided between the inert core and the layercontaining the active ingredient. When the core is comprised of awater-soluble or water-swellable inert material, the sealcoat can be inthe form of a relatively thick layer of a water-insoluble polymer. Sucha controlled release beads may thus comprise: (i) a core unit of asubstantially water-soluble or water-swellable inert material; (ii) afirst layer on the core unit of a substantially water-insoluble polymer;(iii) a second layer covering the first layer and containing an activeingredient; and (iv) a third layer on the second layer of polymereffective for controlled release of the active ingredient, wherein thefirst layer is adapted to control water penetration into the core.

In certain embodiments, the first layer (ii) above usually constitutesmore than about 2% (w/w) of the final bead composition, such as morethan about 3% (w/w), e.g., from about 3% to about 80% (w/w). The amountof the second layer (ii) above usually constitutes from about 0.05% toabout 60% (w/w), such as from about 0.1% to about 30% (w/w) of the finalbead composition. The amount of the third layer (iv) above usuallyconstitutes from about 1% to about 50% (w/w), such as from about 2% toabout 25% (w/w) of the final bead composition. The core unit typicallycan have a size ranging from about 0.05 to about 2 mm. The controlledrelease beads may be provided in a multiple unit formulation, such as acapsule or a tablet.

The cores can comprise a water-soluble or swellable material and may beany such material that is conventionally used as cores or any otherpharmaceutically acceptable water-soluble or water-swellable materialmade into beads or pellets. The cores may be spheres of materials suchas sucrose/starch (Sugar Spheres NF), sucrose crystals, or extruded anddried spheres typically comprised of excipients such as microcrystallinecellulose and lactose. The substantially water-insoluble material in thefirst, or sealcoat layer is generally a “GI insoluble” or “GI partiallyinsoluble” film forming polymer (dispersed or dissolved in a solvent).Examples include, but are not limited to, ethyl cellulose, celluloseacetate, cellulose acetate butyrate, polymethacrylates such as ethylacrylate/methyl methacrylate copolymer (Eudragit® NE-30-D, Eudragit® S,and Eudragit® L) and ammonio methacrylate copolymer types A and B(Eudragit® RL30D, RS30D, Eudragit® RL, and Eudragit® RS), and siliconeelastomers. Usually, a plasticizer is used together with the polymer.Examples of plasticizers include, but are not limited to,dibutylsebacate, propylene glycol, triethylcitrate, tributylcitrate,castor oil, acetylated monoglycerides, acetyl triethylcitrate, acetylbutylcitrate, diethyl phthalate, dibutyl phthalate, triacetin, andfractionated coconut oil (medium-chain triglycerides). The second layercontaining the active ingredient can comprise the active ingredient withor without a polymer as a binder. When used, the binder can behydrophilic and can be water-soluble or water-insoluble. Examples ofpolymers that may be used in the second layer containing the active drugare hydrophilic polymers such as, for example, polyvinylpyrrolidone(PVP), polyalkylene glycol such as polyethylene glycol, gelatine,polyvinyl alcohol, starch and derivatives thereof, cellulose derivativessuch as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose,carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethylcellulose, carboxyethyl cellulose, and carboxymethylhydroxyethylcellulose, acrylic acid polymers, polymethacrylates, or any otherpharmaceutically acceptable polymer. The ratio of drug to hydrophilicpolymer in the second layer can be in the range of from about 1:100 toabout 100:1 (w/w). Suitable polymers for use in the third layer, ormembrane, for controlling the drug release may be selected fromwater-insoluble polymers or polymers with pH-dependent solubility, suchas, for example, ethyl cellulose, hydroxypropylmethyl cellulosephthalate, cellulose acetate phthalate, cellulose acetate trimellitate,polymethacrylates, or mixtures thereof, optionally combined withplasticizers, such as those mentioned above. Optionally, the controlledrelease layer comprises, in addition to the polymers above, othersubstance(s) with different solubility characteristics, to adjust thepermeability and thereby the release rate, of the controlled releaselayer. Examples of polymers that may be used as a modifier togetherwith, for example, ethyl cellulose include, but are not limited to,HPMC, hydroxyethyl cellulose, hydroxypropyl cellulose, methylcellulose,carboxymethylcellulose, polyethylene glycol, polyvinylpyrrolidone (PVP),polyvinyl alcohol, polymers with pH-dependent solubility, such ascellulose acetate phthalate or ammonio methacrylate copolymer andmethacrylic acid copolymer, and mixtures thereof. Additives such assucrose, lactose, and pharmaceutical grade surfactants may also beincluded in the controlled release layer, if desired.

The preparation of a multiple unit formulation can comprise theadditional step of transforming the prepared beads into a pharmaceuticalformulation, such as by filling a predetermined amount of the beads intoa capsule, or compressing the beads into tablets. Examples ofmulti-particulate sustained release oral dosage forms are described in,for example, U.S. Pat. Nos. 6,627,223 and 5,229,135.

In certain embodiments, an oral sustained release pump may be used (seeLanger, supra; Sefton, CRC Crit Ref Biomed. Eng. 1987, 14, 201; Saudeket al., N. Engl. J Med. 1989, 321, 574).

In certain embodiments, polymeric materials can be used (See “MedicalApplications of Controlled Release,” Langer and Wise (eds.), CRC Press.,Boca Raton, Fla. (1974); “Controlled Drug Bioavailability,” Drug ProductDesign and Performance, Smolen and Ball (eds.), Wiley, New York (1984);Langer et al., J Macromol. Sci. Rev. Macromol Chem. 1983, 23, 61; seealso Levy et al., Science 1985, 228, 190; During et al., Ann. Neurol.1989, 25, 351; Howard et al., J. Neurosurg. 1989, 71, 105). In someembodiments, polymeric materials can be used for sustained release oraldelivery. Polymers for sustained release oral delivery include, but arenot limited to, sodium carboxymethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, and hydroxyethylcellulose (especially,hydroxypropylmethylcellulose). Other cellulose ethers have beendescribed (Alderman, Int. J. Pharm. Tech. & Prod. Mfr 1984, 5(3), 1-9).Factors affecting drug release are well known to the skilled artisan andhave been described in the art (Bamba et al., Int. J. Pharm. 1979, 2,307).

In certain embodiments, enteric-coated preparations can be used forsustained release oral administration. Examples of coating materials forenteric-coated preparations include polymers with a pH-dependentsolubility (i.e., pH-controlled release), polymers with a slow orpH-dependent rate of swelling, dissolution or erosion (i.e.,time-controlled release), polymers that are degraded by enzymes (i.e.,enzyme-controlled release), and polymers that form firm layers that aredestroyed by an increase in pressure (i.e., pressure-controlledrelease).

In certain embodiments, drug-releasing lipid matrices can be used forsustained release oral administration. An example is when solidmicroparticles of a compound of the present disclosure are coated with athin controlled release layer of a lipid (e.g., glyceryl behenate and/orglyceryl palmitostearate) as disclosed in Farah et al., U.S. Pat. No.6,375,987 and Joachim et al., U.S. Pat. No. 6,379,700. The lipid-coatedparticles can optionally be compressed to form a tablet. Anothercontrolled release lipid-based matrix material, which is suitable forsustained release oral administration comprises polyglycolizedglycerides as disclosed in Roussin et al., U.S. Pat. No. 6,171,615.

In certain embodiments, waxes can be used for sustained release oraladministration. Examples of suitable sustained compound-releasing waxesare disclosed in Cain et al., U.S. Pat. No. 3,402,240 (caranuba wax,candelilla wax, esparto wax and ouricury wax); Shtohryn et al., U.S.Pat. No. 4,820,523 (hydrogenated vegetable oil, bees wax, caranuba wax,paraffin, candelilla, ozokerite, and mixtures thereof); and Walters,U.S. Pat. No. 4,421,736 (mixture of paraffin and castor wax).

In certain embodiments, osmotic delivery systems are used for oralsustained release administration (Verma et al., Drug Dev. Ind. Pharm.,2000, 26, 695-708). In some embodiments, OROS® systems made by AlzaCorporation, Mountain View, Calif. are used for oral sustained releasedelivery devices (Theeuwes et al., U.S. Pat. No. 3,845,770; Theeuwes etal., U.S. Pat. No. 3,916,899).

In certain embodiments, a controlled-release system can be placed inproximity of the target of at least one compound disclosed herein (e.g.,within the spinal cord), thus requiring only a fraction of the systemicdose (See, e.g., Goodson, in “Medical Applications of ControlledRelease,” supra, vol. 2, pp. 115-138 (1984)). Other controlled-releasesystems discussed in Langer, Science 1990, 249, 1527-1533, may also beused.

In certain embodiments, the dosage form can comprise at least onecompound of the present disclosure coated on a polymer substrate. Thepolymer can be an erodible, or a nonerodible polymer. The coatedsubstrate may be folded onto itself to provide a bilayer polymer drugdosage form. For example, a compound of the present disclosure can becoated onto a polymer such as a polypeptide, collagen, gelatin,polyvinyl alcohol, polyorthoester, polyacetyl, or a polyorthocarbonateand the coated polymer folded onto itself to provide a bilaminateddosage form. In operation, the bioerodible dosage form erodes at acontrolled rate to dispense a compound disclosed herein over a sustainedrelease period. Examples of biodegradable polymers include biodegradablepoly(amides), poly(amino acids), poly(esters), poly(lactic acid),poly(glycolic acid), poly(carbohydrate), poly(orthoester),poly(orthocarbonate), poly(acetyl), poly(anhydrides), biodegradablepoly(dihydropyrans), and poly(dioxinones), which are known in the art(Rosoff, Controlled Release of Drugs Chap. 2, pp. 53-95 (1989); and inU.S. Pat. Nos. 3,811,444; 3,962,414; 4,066,747, 4,070,347; 4,079,038;and 4,093,709).

In certain embodiments, a dosage form comprises at least one compound ofthe present disclosure loaded into a polymer that releases the compoundby diffusion through a polymer, by flux through pores, or by rupture ofa polymer matrix. The drug delivery polymeric dosage form can comprisefrom between about 2 mg to about 500 mg of at least one compound of thepresent disclosure homogenously contained in or on a polymer. A dosageform can comprise at least one exposed surface at the beginning of dosedelivery. The non-exposed surface, when present, can be coated with apharmaceutically acceptable material impermeable to the passage of acompound of the present disclosure. Such dosage forms can bemanufactured by procedures known in the art. An example of providing adosage form comprises blending a pharmaceutically acceptable carriersuch as polyethylene glycol, with a known dose of a compound at anelevated temperature, (e.g., 37° C.), and adding it to a silasticmedical grade elastomer with a cross-linking agent, for example,octanoate, followed by casting in a mold. The step is repeated for eachoptional successive layer. The system is allowed to set for about 1hour, to provide the dosage form. Examples of polymers for manufacturinga dosage form include olefinic polymers, vinyl polymers, additionpolymers, condensation polymers, carbohydrate polymers, and siliconepolymers such as polyethylene, polypropylene, polyvinyl acetate,polymethylacrylate, polyisobutylmethacrylate, poly alginate, polyamide,and polysilicone. The polymers and procedures for manufacturing them aredescribed in the art (Coleman et al., Polymers 1990, 31, 1187-1231;Roerdink et al., Drug Carrier Systems 1989, 9, 57-10; Leong et al., Adv.Drug Delivery Rev. 1987, 1, 199-233; Roff et al., Handbook of CommonPolymers 1971, CRC Press; and U.S. Pat. No. 3,992,518).

In certain embodiments, the dosage from can comprise a plurality ofpills. Time-release pills can provide a number of individual doses forproviding various time doses for achieving a sustained-release prodrugdelivery profile over an extended period of time up to about 24 hours.The matrix can comprise a hydrophilic polymer such as, for example, apolysaccharide, agar, agarose, natural gum, alkali alginate includingsodium alginate, carrageenan, fucoidan, furcellaran, laminaran, hypnea,gum arabic, gum ghatti, gum karaya, grum tragacanth, locust bean gum,pectin, amylopectin, gelatin, or a hydrophilic colloid. The hydrophilicmatrix can comprise a plurality of from about 4 to about 50 pills, eachpill comprise a dose population of about 10 ng, about 0.5 mg, about 1mg, about 1.2 mg, about 1.4 mg, about 1.6 mg, about 5.0 mg, etc. Thepills can comprise a release rate-controlling wall of 0.001 mm up to 10mm thickness to provide for the timed release of a compound. Examples ofwall forming materials include triglyceryl esters such as glyceryltristearate, glyceryl monostearate, glyceryl dipalmitate, glyceryllaureate, glyceryl didecenoate, and glyceryl tridenoate. Other wallforming materials comprise polyvinyl acetate, phthalate, methylcellulosephthalate, and microporous olefins. Procedures for manufacturing pillsare disclosed in U.S. Pat. Nos. 4,434,153; 4,721,613; 4,853,229;2,996,431; 3,139,383 and 4,752,470.

In certain embodiments, a dosage form can comprise an osmotic dosageform, which comprises a semipermeable wall that surrounds a therapeuticcomposition comprising the compound. In use within a patient, theosmotic dosage form comprising a homogenous composition, imbibes fluidthrough the semipermeable wall into the dosage form in response to theconcentration gradient across the semipermeable wall. The therapeuticcomposition in the dosage form develops osmotic pressure differentialthat causes the therapeutic composition to be administered through anexit from the dosage form over a prolonged period of time up to about 24hours (or even in some cases up to about 30 hours) to provide controlledand sustained compound release. These delivery platforms can provide anessentially zero order delivery profile as opposed to the spikedprofiles of immediate release formulations.

In certain embodiments, a dosage form can comprise another osmoticdosage form comprising a wall surrounding a compartment, the wallcomprising a semipermeable polymeric composition permeable to thepassage of fluid and substantially impermeable to the passage ofcompound present in the compartment, a compound-containing layercomposition in the compartment, a hydrogel push layer composition in thecompartment comprising an osmotic formulation for imbibing and absorbingfluid for expanding in size for pushing the compound composition layerfrom the dosage form, and at least one passageway in the wall forreleasing the prodrug composition. The dosage form can deliver acompound by imbibing fluid through the semipermeable wall at a fluidimbibing rate determined by the permeability of the semipermeable walland the osmotic pressure across the semipermeable wall causing the pushlayer to expand, thereby delivering the compound from the dosage formthrough the exit passageway to a patient over a prolonged period of time(up to about 24 or even about 30 hours). The hydrogel layer compositioncan comprise from about 10 mg to about 1000 mg of a hydrogel such as apolyalkylene oxide of about 1,000,000 to about 8,000,000 weight-averagemolecular weight, for example, a polyethylene oxide of about 1,000,000weight-average molecular weight, a polyethylene oxide of about 2,000,000molecular weight, a polyethylene oxide of about 4,000,000 molecularweight, a polyethylene oxide of about 5,000,000 molecular weight, apolyethylene oxide of about 7,000,000 molecular weight, and apolypropylene oxide of the about 1,000,000 to about 8,000,000weight-average molecular weight; or from about 10 mg to about 1000 mg ofan alkali carboxymethylcellulose of about 10,000 to about 6,000,000weight average molecular weight, such as sodium carboxymethylcelluloseor potassium carboxymethylcellulose. The hydrogel expansion layercomprises 0.0 mg to 350 mg, in present manufacture; from about 0.1 mg toabout 250 mg of a hydroxyalkylcellulose of about 7,500 to about 4,500,00weight-average molecular weight (e.g., hydroxymethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose, orhydroxypentylcellulose) in present manufacture; from about 1 mg to about50 mg of an agent such as sodium chloride, potassium chloride, potassiumacid phosphate, tartaric acid, citric acid, raffinose, magnesiumsulfate, magnesium chloride, urea, inositol, sucrose, glucose, orsorbitol; from about 0 to about 5 mg of a colorant, such as ferricoxide; from about 0 mg to about 30 mg, in a present manufacture, fromabout 0.1 mg to about 30 mg of a hydroxypropylalkylcellulose of about9,000 to about 225,000 average-number molecular weight, such as, forexample, hydroxypropylethylcellulose, hydroxypropypentylcellulose,hydroxypropylmethylcellulose, and hydropropylbutylcellulose; from about0.00 to about 1.5 mg of an antioxidant such as ascorbic acid, butylatedhydroxyanisole, butylated hydroxyquinone, butylhydroxyanisol,hydroxycoumarin, butylated hydroxytoluene, cephalm, ethyl gallate,propyl gallate, octyl gallate, lauryl gallate, propyl-hydroxybenzoate,trihydroxybutylrophenone, dimethylphenol; dibutylphenol, vitamin E,lecithin, or ethanolamine; and 0.0 mg to 7 mg of a lubricant such ascalcium stearate, magnesium stearate, zinc stearate, magnesium oleate,calcium palmitate, sodium suberate, potassium laurate, salts of fattyacids, salts of alicyclic acids, salts of aromatic acids, stearic acid,oleic acid, palmitic acid, a mixture of a salt of a fatty, alicyclic oraromatic acid, and a fatty, alicyclic, or aromatic acid.

In the osmotic dosage forms, the semipermeable wall can comprise acomposition that is permeable to the passage of fluid and impermeable tothe passage of prodrug. The wall is nontoxic and comprises a polymersuch as cellulose acylate, cellulose diacylate, cellulose triacylate,cellulose acetate, cellulose diacetate, or cellulose triacetate. Thewall can comprise from about 75 wt % (weight percent) to about 100 wt %of the cellulosic wall-forming polymer or, the wall can compriseadditionally from about 0.01 wt % to about 80 wt % of polyethyleneglycol, or from about 1 wt % to about 25 wt % of a cellulose ether suchas hydroxypropylcellulose or a hydroxypropylalkycellulose such ashydroxypropylmethylcellulose. The total weight percent of all componentscomprising the wall is equal to 100 wt %. The internal compartment cancomprise the compound-containing composition alone or in layeredposition with an expandable hydrogel composition. The expandablehydrogel composition in the compartment can increase in dimension byimbibing the fluid through the semipermeable wall, causing the hydrogelto expand and occupy space in the compartment, whereby the drugcomposition is pushed from the dosage form. The therapeutic layer andthe expandable layer act together during the operation of the dosageform for the release of prodrug to a patient over time. The dosage formcan comprise a passageway in the wall that connects the exterior of thedosage form with the internal compartment. The osmotic powered dosageform can be made to deliver prodrug from the dosage form to the patientat a zero order rate of release over a period of up to about 24 hours.

The expression “passageway” as used herein can comprise means andmethods suitable for the metered release of the compound from thecompartment of the dosage form. The exit means can comprise at least onepassageway, including orifice, bore, aperture, pore, porous element,hollow fiber, capillary tube, channel, porous overlay, or porous elementthat provides for the osmotic controlled release of compound. Thepassageway can include a material that erodes or is leached from thewall in a fluid environment of use to produce at least onecontrolled-release dimensioned passageway. Examples of materialssuitable for forming a passageway, or a multiplicity of passagewaysinclude a leachable poly(glycolic) acid or poly(lactic) acid polymer inthe wall, a gelatinous filament, poly(vinyl alcohol), leach-ablepolysaccharides, salts, and oxides. A pore passageway, or more than onepore passageway, can be formed by leaching a leachable compound, such assorbitol, from the wall. The passageway can have controlled-releasedimensions, such as round, triangular, square and elliptical, for themetered release of prodrug from the dosage form. The dosage form can beconstructed with one or more passageways in spaced apart relationship ona single surface or on more than one surface of the wall. The expression“fluid environment” denotes an aqueous or biological fluid as in a humanpatient, including the gastrointestinal tract. Passageways and equipmentfor forming passageways are disclosed in U.S. Pat. Nos. 3,845,770;3,916,899; 4,063,064; 4,088,864; and 4,816,263. Passageways formed byleaching are disclosed in U.S. Pat. Nos. 4,200,098 and 4,285,987.

Regardless of the specific form of sustained release oral dosage formused, in certain embodiments, compounds can be released from the dosageform over a period of at least about 4 hours, at least about 8 hours, atleast about 12 hours, at least about 16 hours at least about 20 hours,and in certain embodiments, at least about 24 hours. In certainembodiments, a dosage form can release from about 0% to about 30% of theprodrug in about 0 to about 2 hours, from about 20% to about 50% of theprodrug in about 2 to about 12 hours, from about 50% to about 85% of theprodrug in about 3 to about 20 hours and greater than about 75% of theprodrug in about 5 to about 18 hours. A sustained release oral dosageform of the present disclosure can further provide a concentration of3-aminopropylsulfinic acid or analog thereof in the plasma and/or bloodof a patient over time, which curve has an area under the curve (AUC)that is proportional to the dose of the prodrug of 3-aminopropylsulfinicacid or analog thereof administered, and a maximum concentrationC_(max). The C_(max) is less than about 75%, such as less than about60%, of the C_(max) obtained from administering an equivalent dose ofthe compound from an immediate release oral dosage form and the AUC issubstantially the same as the AUC obtained from administering anequivalent dose of the prodrug from an immediate release oral dosageform.

In certain embodiments, compositions or dosage forms of the presentdisclosure can be administered once or twice per day, and in certainembodiments, once per day.

Uses of Compounds, Compositions, and Dosage Forms

In certain embodiments, a therapeutically effective amount of one ormore compounds of Formula (I) can be administered to a patient, such asa human, suffering from stiffness, involuntary movements, and/or painassociated with spasticity. The underlying etiology of the spasticitybeing so treated may have a multiplicity of origins, including, e.g.,cerebral palsy, multiple sclerosis, stroke, and head and spinal cordinjuries. In certain embodiments, a therapeutically effective amount ofone or more compounds of Formula (I) can be administered to a patient,such as a human, suffering from gastroesophageal reflux disease. Incertain embodiments, a therapeutically effective amount of one or morecompounds of Formula (I) can be administered to a patient, such as ahuman, suffering from emesis. In certain embodiments, a therapeuticallyeffective amount of one or more compounds of Formula (I) can beadministered to a patient, such as a human, suffering from cough. Incertain embodiments, a therapeutically effective amount of one or morecompounds of Formula (I) can be administered to a patient, such as ahuman, suffering from drug addiction. Addiction to stimulants such ascocaine or amphetamines, or narcotics such as morphine or heroin may beeffectively treated by administration of one or more compounds ofFormula (I). In certain embodiments, a therapeutically effective amountof one or more compounds of Formula (I) can be administered to apatient, such as a human, suffering from alcohol abuse or addiction, ornicotine abuse or addiction. In certain of the above embodiments,sustained release oral dosage forms comprising a therapeuticallyeffective amount of one or more compounds of Formula (I) can beadministered to the patients.

Further, in certain embodiments, a therapeutically effective amount ofone or more compounds of Formula (I) can be administered to a patient,such as a human, as a preventative measure against various diseases ordisorders. Thus, a therapeutically effective amount of one or morecompounds of Formula (I) can be administered as a preventative measureto a patient having a predisposition for spasticity, gastroesophagealreflux disease, emesis, cough, alcohol addiction or abuse, nicotineaddiction or abuse, or other drug addiction or abuse.

When used to treat or prevent the above diseases or disorders atherapeutically effective amount of one or more compounds of Formula (I)may be administered or applied singly, or in combination with otheragents including pharmaceutically acceptable vehicles and/orpharmaceutically active agent for treating a disease or disorder, whichmay be the same or different disease or disorder as the disease ordisorder being treated by the one or more compounds of Formula (I). Atherapeutically effective amount of one or more compounds of Formula (I)may be delivered together with a compound disclosed herein or incombination with another pharmaceutically active agent. For example, inthe treatment of a patient suffering from gastroesophageal refluxdisease, a dosage form comprising a compound of Formula (I) may beadministered in conjunction with a proton pump inhibitor, such asomeprazole, esomeprazole, pantoprazole, lansoprazole, or rabeprazolesodium, or with an H₂ antagonist such as rantidine, cimetidine, orfamotidine.

Dosage forms, upon releasing a prodrug of 3-aminopropylsulfinic acid oranalog thereof, can provide the corresponding 3-aminopropylsulfinic acidor analog thereof upon in vivo administration to a patient. Thepromoiety or promoieties of the prodrug may be cleaved either chemicallyand/or enzymatically. One or more enzymes present in the stomach,intestinal lumen, intestinal tissue, blood, liver, brain, or any othersuitable tissue of a mammal may enzymatically cleave the promoiety orpromoieties of the prodrug. If the promoiety or promoieties are cleavedafter absorption by the gastrointestinal tract, the prodrugs of3-aminopropylsulfinic acid or analogs thereof may have the opportunityto be absorbed into the systemic circulation from the large intestine.In certain embodiments, the promoiety or promoieties are cleaved afterabsorption by the gastrointestinal tract.

The promoiety of a 3-aminopropylsulfinic acid analog prodrug of Formula(I) may be cleaved prior to absorption by the gastrointestinal tract(e.g., within the stomach or intestinal lumen) and/or after absorptionby the gastrointestinal tract (e.g., in intestinal tissue, blood, liver,or other suitable tissue of a mammal). In certain embodiments,3-aminopropylsulfinic acid or analog thereof remains conjugated to theprodrug promoiety during transit across the intestinal mucosal barrierto provide protection from presystemic metabolism. In certainembodiments, a prodrug of 3-aminopropylsulfinic acid or analog thereofof Formula (I) is essentially not metabolized to the corresponding3-aminopropylsulfinic acid or analog thereof of Formula (II) withinenterocytes but is metabolized to the patent drug within the systemiccirculation. Cleavage of the promoiety of the prodrug of3-aminopropylsulfinic acid or analog thereof of Formula (I) afterabsorption by the gastrointestinal tract may allow these prodrugs to beabsorbed into the systemic circulation either by active transport,passive diffusion, or by a combination of both active and passiveprocesses. Accordingly, in certain embodiments, a pharmaceuticalcomposition, formulation, or dosage form of the present disclosure iscapable of maintaining a therapeutically effective concentration of3-aminopropylsulfinic acid or analog thereof in the plasma or blood of apatient for a time period of at least about 4 hours, for at least about8 hours, for a period of at least about 12 hours, at least about 16hours, at least about 20 hours, and in certain embodiments for at leastabout 24 hours, after the pharmaceutical composition, formulation, ordosage form comprising a corresponding prodrug of 3-aminopropylsulfinicacid or analog thereof of Formula (I) and a pharmaceutically acceptablevehicle is orally administered to the patient.

In certain embodiments, a prodrug of a 3-aminopropylsulfinic acid oranalog thereof of Formula (I) is selected from a prodrug of:

-   3-aminopropylsulfinic acid;-   (3-amino-2-(4-chlorophenyl)propyl)sulfinic acid;-   (3-amino-2-hydroxypropyl)sulfinic acid;-   (2S)-(3-amino-2-hydroxypropyl)sulfinic acid;-   (2R)-(3-amino-2-hydroxypropyl)sulfinic acid;-   (3-amino-2-fluoropropyl)sulfinic acid;-   (2S)-(3-amino-2-fluoropropyl)sulfinic acid;-   (2R)-(3-amino-2-fluoropropyl)sulfinic acid; and    (3-amino-2-oxopropyl)sulfinic acid;

and pharmaceutically acceptable salts thereof, and pharmaceuticallyacceptable solvates of any of the foregoing.

Prodrugs of 3-aminopropylsulfinic acid and analogs thereof of Formula(I) or pharmaceutically acceptable salts thereof, or pharmaceuticallyacceptable solvates of any of the foregoing as disclosed herein, and/orpharmaceutical compositions thereof can be administered orally. Prodrugsof 3-aminopropylsulfinic acid and analogs thereof of Formula (I) and/orpharmaceutical compositions thereof can also be administered by anyother convenient route, for example, by infusion or bolus injection, byabsorption through epithelial or mucocutaneous linings (e.g., oralmucosa, rectal, and intestinal mucosa, etc.). Administration can besystemic or local. Various delivery systems are known, (e.g.,encapsulation in liposomes, microparticles, microcapsules, capsules,etc.) that can be used to administer a compound and/or pharmaceuticalcomposition. Methods of administration include, but are not limited to,intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous,intranasal, epidural, oral, sublingual, intranasal, intracerebral,intravaginal, transdermal, rectally, inhalation, or topically,particularly to the ears, nose, eyes, or skin.

In certain embodiments, it may be desirable to introduce a prodrug of3-aminopropylsulfinic acid or analog thereof of Formula (I) and/orpharmaceutical compositions thereof into the central nervous system byany suitable route, including intraventricular, intrathecal, andepidural injection. An intraventricular catheter may facilitateintraventricular injection, and can be, for example, attached to areservoir, such as an Ommaya reservoir.

In certain embodiments, prodrugs of 3-aminopropylsulfinic acid andanalogs thereof of Formula (I) and/or pharmaceutical compositionsthereof can be delivered via sustained release systems, such as oralsustained release systems. In certain embodiments, a pump may be used(Langer, supra; Sefton, 1987 CRC Crit. Ref Biomed Eng. 14:201; Saudek etal., 1989 N. Engl. J Med. 321:574).

Doses

Prodrugs of 3-aminopropylsulfinic acid or analogs thereof of Formula (I)can be administered to treat or prevent diseases or disorders such asspasticity, gastroesophageal reflux disease, emesis, cough, alcoholaddiction or abuse, nicotine addiction or abuse, or other drug addictionor abuse.

The amount of a compound of Formula (I) that will be effective in thetreatment of a particular disease or disorder disclosed herein willdepend on the nature of the disease or disorder, and can be determinedby standard clinical techniques known in the art. In addition, in vitroor in vivo assays may optionally be employed to help identify optimaldosage ranges. The amount of a compound administered will, of course,depend on, among other factors, the subject being treated, the weight ofthe subject, the severity of the disease or disorder, the manner ofadministration, and the judgment of the prescribing physician.

In certain embodiments, dosage forms can be adapted to be administeredto a patient no more than twice per day, and in certain embodiments,only once per day. Dosing may be provided alone or in combination withother drugs and may continue as long as required for effective treatmentof the disease state or disorder.

Suitable dosage ranges for oral administration can depend on the potencyof the parent 3-aminopropylsulfinic acid or analog thereof. For certain3-aminopropylsulfinic acid analogs, doses are generally between about0.15 mg to about 20 mg per kilogram body weight. Certain3-aminopropylsulfinic acid analogs may be more potent and lower dosesmay be appropriate for both the parent drug and any prodrug (measured onan equivalent molar basis). Dosage ranges may be readily determined bymethods known to the skilled artisan.

Combination Therapy

In certain embodiments, prodrugs of 3-aminopropylsulfinic acid oranalogs thereof of Formula (I) or pharmaceutically acceptable saltsthereof, or pharmaceutically acceptable solvates of any of the foregoingcan be used in combination therapy with at least one other therapeuticagent. Prodrugs of 3-aminopropylsulfinic acid or analogs thereof ofFormula (I) and the at least one other therapeutic agent(s) can actadditively or, in certain embodiments, synergistically. In certainembodiments, prodrugs of 3-aminopropylsulfinic acid or analogs thereofof Formula (I) can be administered concurrently with the administrationof another therapeutic agent. In certain embodiments, prodrugs of3-aminopropylsulfinic acid or analogs thereof of Formula (I) orpharmaceutically acceptable salts thereof, or solvates of any of theforegoing can be administered prior or subsequent to administration ofanother therapeutic agent. The at least one other therapeutic agent canbe effective for treating the same or different disease, disorder, orcondition.

Methods of the present disclosure include administration of one or morecompounds or pharmaceutical compositions of the present disclosure andone or more other therapeutic agents provided that the combinedadministration does not inhibit the therapeutic efficacy of the one ormore compounds of the present disclosure and/or does not produce adversecombination effects.

In certain embodiments, compositions of the present disclosure can beadministered concurrently with the administration of another therapeuticagent, which can be part of the same pharmaceutical composition as, orin a different composition from, that containing the compounds of thepresent disclosure. In certain embodiments, compounds of the presentdisclosure can be administered prior or subsequent to administration ofanother therapeutic agent. In certain embodiments of combinationtherapy, the combination therapy comprises alternating betweenadministering a composition of the present disclosure and a compositioncomprising another therapeutic agent, e.g., to minimize adverse sideeffects associated with a particular drug. When a compound of thepresent disclosure is administered concurrently with another therapeuticagent that potentially can produce adverse side effects including, butnot limited to, toxicity, the therapeutic agent can advantageously beadministered at a dose that falls below the threshold at which theadverse side effect is elicited.

In certain embodiments, a pharmaceutical composition can furthercomprise substances to enhance, modulate and/or control release,bioavailability, therapeutic efficacy, therapeutic potency, stability,and the like. For example, to enhance therapeutic efficacy a compound ofthe present disclosure, the compound can be co-administered with one ormore active agents to increase the absorption or diffusion of thecompound from the gastrointestinal tract, or to inhibit degradation ofthe drug in the systemic circulation. In certain embodiments, at leastone compound of the present disclosure can be co-administered withactive agents having a pharmacological effect that enhance thetherapeutic efficacy of the drug.

In certain embodiments, compounds or pharmaceutical compositions of thepresent disclosure include, or can be administered to a patient togetherwith, another compound for treating or preventing spasticity, drugs fortreating or preventing gastroesophageal reflux disease, drugs fortreating or preventing narcotic addiction or abuse, drugs for treatingor preventing alcohol addiction or abuse, drugs for treating orpreventing nicotine addiction or abuse, or drugs for treating orpreventing emesis or cough.

Examples of drugs for treating or preventing movement disorders such asspasticity include levodopa, mild sedatives such as benzodiazepinesincluding alprazolam, chlordiazepoxide, clonazepam, clorazepate,diazepam, lorazepam, and oxazepam; muscle relaxants such as baclofen,anticholinergic drugs such as trihexyphenidyl and diphenhydramine;antipsychotics such as chlorpromazine, fluphenazine, haloperidol,loxapine, mesoridazine, molindone, perphenazine, pimozide, thioridazine,thiothixene, trifluoperazine, aripiprazole, clozapine, olanzapine,quetiapine, risperidone, and ziprasidone; and antidepressants such asamitriptyline.

Examples of drugs for treating or preventing gastrointestinal disorderssuch as gastroesophageal reflux disease include H2 inhibitors such ascimetidine, famotidine, nizatidine, and ranitidine; proton pumpinhibitors such as omeprazole, lansoprazole, pantoprazole, rabeprazole,and esomeprazole; and prokinetics such as cisparide, bethanechol, andmetoclopramide.

Examples of drugs for treating or preventing emesis (nausea andvomiting) include benzamines such as metoclopramide; phenothiazines suchas prochlorperazine, perphenazine, chlorpromazine, promethazine, andthiethylperazine; butyrophenones such as droperidol and haloperidol;dopamine 2 antagonists such as metoclorpamide; 5-HT3 antagonists such asondansetron, granisetron, dolasetron, palonosetron; NK-1 receptorantagonists such as aprepitant, corticosteroids such as dexamethazone;antihistamines such as diphenhydramine and hydroxyzine; cannabinoidssuch as dronabinol; and benzodiazepines such as lorazepam, midazolam,alprazolam, and olanzapine

Examples of drugs for treating or preventing alcohol addiction or abuseinclude disulfiram, naltrexone, acamprosate, clonidine, methadone,1-alpha-acetylmethadol, buprenorphine, bupropion, and baclofen.

Examples of drugs for treating or preventing narcotic addiction or abuseinclude buprenorphine, tramadol, methadone, and naltrexone.

Examples of drugs for treating or preventing nicotine addiction or abuseinclude bupropion, clonidine, and nicotine.

Examples of drugs for treating or preventing cough include codeine,dextromethorphan, guaifenesin, hydrocodone, hydromorphone, benzonatate,diphenhydramine, pseudoephedrine, acetaminophen, and carbinoxamine.

EXAMPLES

The following examples describe in detail preparation of compounds andcompositions of the present disclosure and protocols for using compoundsand compositions of the present disclosure. It will be apparent to thoseof ordinary skill in the art that many modifications, both to materialsand methods, may be practiced without departing from the scope of thedisclosure.

In the examples below, the following abbreviations have the followingmeanings. If an abbreviation is not defined, it has its generallyaccepted meaning.

-   -   g=gram    -   h=hour    -   HPLC=high pressure liquid chromatography    -   L=liter    -   LC/MS=liquid chromatography/mass spectroscopy    -   M=molar    -   mg=milligram    -   min=minute    -   mL=milliliter    -   mm=millimeter    -   mmol=millimoles    -   mol=moles    -   THF=tetrahydrofuran    -   μg=microgram    -   μL=microliter    -   μM=micromolar    -   v/v=volume to total volume    -   w/v=weight to total volume    -   w/w=weight to total weight        In the examples below, Examples 2-8, 10-12, 14-20, and 23-84 are        prophetic.

Example 1 O-(1-Isobutanoyloxyethyl) S-Methyl Thiocarbonate (2) Step A:O-(1-Chloroethyl) S-Methyl Thiocarbonate (3)

A 21% (w/w) aqueous solution of sodium methylthiolate (580.7 g, 1.74mol) was added to a solution of 1-chloroethyl chloroformate (250 g, 1.74mol) and tetrabutylammonium hydrogensulfate (5.9 g, 17 mmol) in CH₂Cl₂(450 mL) over 2 h. The reaction mixture was stirred for an additionalhour, then worked-up by separating the aqueous phase and extracting theorganic phase with brine (2×250 mL). The organic phase was dried overanhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by vacuum distillation to afford the title compound (3) as acolorless liquid (277.3 g, 97% yield). ¹H NMR (CDCl₃, 400 MHz): δ 1.82(d, J=5.6 Hz, 3H), 2.38 (s, 3H), 6.57 (q, J=5.2 Hz, 1H).

Step B: O-(1-Isobutanoyloxyethyl) S-Methyl Thiocarbonate (2)

Compound (3) (308 g, 2 mol) was dissolved in isobutyric acid (264 g, 3mol). This mixture was slowly added to a pre-mixed solution ofisobutyric acid (264 g, 3 mol) and diisopropylethylamine (387 g, 3 mol),and the reaction mixture heated to 55° C. for 16 h, diluted with ether(10 L), washed with water (4×5 L), saturated bicarbonate solution (2×5L), and brine (5 L), then dried over anhydrous sodium sulfate, filtered,and concentrated in vacuo to give the title compound (2) as a colorlessliquid (400 g, 97% yield). The product was optionally further purifiedby vacuum distillation (135° C./20 Torr). ¹H NMR (CDCl₃, 400 MHz): δ1.17 (d, J=6.8 Hz, 6H), 1.49 (d, J=5.6 Hz, 3H), 2.33 (s, 3H), 2.54 (m,1H), 6.91 (q, J=5.2 Hz, 1H).

Example 2 O-(1-Butanoyloxyethyl) S-Methyl Thiocarbonate (4)

Following the procedures of Example 1 and replacing isobutyric acid withn-butyric acid in Step B affords the title compound (4) as an oil.

Example 3 O-(1-Pivaloyloxyethyl) S-Methyl Thiocarbonate (5

Following the procedures of Example 1 and replacing isobutyric acid withpivalic acid in Step B affords the title compound (5) as an oil.

Example 4 O-(1-Cyclohexanoyloxyethyl) S-Methyl Thiocarbonate (6)

Following the procedures of Example 1 and replacing isobutyric acid withcyclohexanecarboxylic acid in Step B affords the title compound (6) asan oil.

Example 5 O-(Isobutanoyloxymethyl) S-Methyl Thiocarbonate (7)

Following the procedures of Example 1 and replacing 1-chloroethylchloroformate with chloromethyl chloroformate in Step A affords thetitle compound (7) as an oil.

Example 6 O-(Butanoyloxymethyl) S-Methyl Thiocarbonate (8)

Following the procedures of Example 2 and replacing 1-chloroethylchloroformate with chloromethyl chloroformate in Step A affords thetitle compound (8) as an oil.

Example 7 O-(Pivaloyloxymethyl) S-Methyl Thiocarbonate (9)

Following the procedures of Example 3 and replacing 1-chloroethylchloroformate with chloromethyl chloroformate in Step A affords thetitle compound (9) as an oil.

Example 8 O-(Cyclohexanoyloxymethyl) S-Methyl Thiocarbonate (10)

Following the procedures of Example 4 and replacing 1-chloroethylchloroformate with chloromethyl chloroformate in Step A affords thetitle compound (10) as an oil.

Example 9 Synthesis of O-(1-Isobutanoyloxyisobutoxy) S-MethylThiocarbonate (11) Step A: O-(1-Chloroisobutoxy) S-Methyl Thiocarbonate(12)

A solution of 1-chloro-2-methylpropyl chloroformate (1026 g, 6.0 mol)and tetrabutylammonium hydrogensulfate (20 g, 60 mmol) indichloromethane (1500 mL) in a jacketed 10 L reactor equipped with amechanical stirrer, temperature probe, and addition funnel was cooled to10° C. To the reaction mixture was gradually added a 15% aqueoussolution of sodium methylthiolate (3 L, 6.4 mol) over 4 h. The reactionwas moderately exothermic and the internal temperature was maintainedbetween 10° C. and 20° C. during the addition. The aqueous phase wasseparated and the organic phase was washed with brine (2×2 L) and water(2 L). The organic layer was dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure to afford the title compound (12)(1050 g, 5.76 mol, 96% yield) as a colorless liquid. ¹H NMR (CDCl₃, 400MHz): δ 1.1 (dd, 6H), 2.2 (m, 1H), 2.4 (s, 3H), 6.35 (d, 1H).

Step B: Tetramethylammonium Isobutyrate (13)

To a 20 L round bottom flask was added isobutyric acid (1300 mL, 14mol), and an aqueous solution of 25% tetramethylammonium hydroxide (5 L,14 mol). The water was removed under reduced pressure and azeotropedwith toluene (2×2 L) to leave the product (13) as an amber liquid, whichwas used without further purification.

Step C: O-(1-Isobutanoyloxyisobutoxy) S-Methyl Thiocarbonate (11)

To a 3 L three neck round bottom flask equipped with a mechanicalstirrer and teflon-coated thermocouple was added compound (13) (1672 g,9 mol), isobutyric acid (264 g, 1.5 mol), and compound (12) (1050 g,5.76 mol). The reaction mixture was heated to 80° C. for 12 h and theprogress of the reaction monitored by ¹H NMR. The reaction mixture wascooled to 20° C., diluted with EtOAc (1 L) and sequentially washed withwater (2×1 L), saturated NaHCO₃ (1×2 L), and water (I L). The organicphase was separated and concentrated under reduced pressure to affordthe title compound (11) (905 g, 3.9 mol, 65% yield) as a colorlessliquid. ¹H NMR (CDCl₃, 400 MHz): δ 1.0 (d, 6H), 1.2 (dd, 6H), 2.05 (m,1H), 2.35 (s, 3H), 2.6 (m, 1H), 6.7 (d, 1H).

Example 10 O-(1-Butanoyloxyisobutoxy) S-Methyl Thiocarbonate (14)

Following the procedures of Example 9 and replacing isobutyric acid withn-butyric acid affords the title compound (14) as an oil.

Example 11 O-(1-Pivaloyloxyisobutoxy) S-Methyl Thiocarbonate (15)

Following the procedures of Example 9 and replacing isobutyric acid withpivalic acid affords the title compound (15) as an oil.

Example 12 O-(1-Cyclohexanoyloxyisobutoxy) S-Methyl Thiocarbonate (16)

Following the procedures of Example 9 and replacing isobutyric acid withcyclohexanecarboxylic acid affords the title compound (16) as an oil.

Example 13 [(1-Isobutanoyloxyethoxy)carbonyloxy] Succinimide (17)

To a solution of compound (2) (1 g, 4.8 mmol) in CH₂Cl₂ (10 mL) wasadded N-hydroxysuccinimide (1.1 g, 9.5 mmol) and the reaction mixturecooled to 0° C. A solution of 32% (v/v) peracetic acid in acetic acid(3.4 mL, 1.1 g, 14.4 mmol) was added dropwise over a period of 10 min,then the solution allowed to stir at room temperature for 3 h. Thereaction mixture was diluted with ether (50 mL) and sequentially washedwith water (2×10 mL), saturated sodium bicarbonate solution (10 mL), andbrine (10 mL), then dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo to give the title compound (17) as a colorless oil(1 g, 77% yield). After trituration with hexane (20 mL) the productsolidified to a white solid. m.p: 50-54° C. ¹H NMR (CDCl₃, 400 MHz):1.17 (d, J=6.8 Hz, 6H), 1.56 (d, J=5.6 Hz, 3H), 2.55 (m, 1H), 2.82 (s,4H), 6.80 (q, J=5.2 Hz, 1H). MS (ESI) m/z 296.4 (M+Na)⁺.

Example 14 [(1-Butanoyloxyethoxy)carbonyloxy] Succinimide (18)

Following the procedures of Example 13 and replacing compound (2) withcompound (4) affords the title compound (18).

Example 15 [(1-Pivaloyloxyethoxy)carbonyloxy] Succinimide (19)

Following the procedures of Example 13 and replacing compound (2) withcompound (5) affords the title compound (19).

Example 16 [(1-Cyclohexanoyloxyethoxy)carbonyloxy] Succinimide (20)

Following the procedures of Example 13 and replacing compound (2) withcompound (6) affords the title compound (20).

Example 17 [(Isobutanoyloxymethoxy)carbonyloxy] Succinimide (21)

Following the procedures of Example 13 and replacing compound (2) withcompound (7) affords the title compound (21).

Example 18 [(Butanoyloxymethoxy)carbonyloxy] Succinimide (22)

Following the procedures of Example 13 and replacing compound (2) withcompound (8) affords the title compound (22).

Example 19 [(Pivaloyloxymethoxy)carbonyloxy] Succinimide n

Following the procedures of Example 13 and replacing compound (2) withcompound (9) affords the title compound (23).

Example 20 [(Cyclobexanoyloxymethoxy)carbonyloxy] Succinimide (24)

Following the procedures of Example 13 and replacing compound (2) withcompound (10) affords the title compound (24).

Example 21 Synthesis of(1R)-1-[((3S,4S)-2,5-Dioxo-3,4-dibenzoyloxypyrrolidinyl)-oxycarbonyloxy]-2-methylpropyl2-methylpropanoate (25) Step A:(3S,4S)-2,5-Dioxo-3,4-dibenzoyloxy-3,4-dihydrofuran (26)

A suspension of 2,3-dibenzoyl-D-tartaric acid (100 g, 279 mmol) inacetic anhydride (300 mL) was stirred at 85° C. for 2 h then thereaction mixture allowed to cool to room temperature. The crystallineproduct was collected by filtration, washed with a mixture of ether andhexane (1:1), and dried under vacuum to afford the title compound (26)(80 g, 84% yield). ¹H NMR (CDCl₃, 400 MHz): δ 5.99 (s, 2H), 7.50 (m,4H), 7.66 (m, 2H), 8.07 (m, 4H).

Step B: 1-Hydroxy-(3S,4S)-2,5-Dioxo-3,4-dibenzoyloxypyrrolidine (27)

To a suspension of compound (26) (60 g, 176 mmol) in a mixture ofacetonitrile and water (8:1, 400 mL) at 0° C. was added a 50% aqueoussolution of hydroxylamine (13.0 mL, 211 mmol). The resulting suspensionwas stirred overnight at room temperature to obtain a clear solution.The bulk of the acetonitrile was removed by rotary evaporation and theresidue was portioned between ethyl acetate and water. The organic phasewas washed sequentially with water and brine, dried over anhydrousNa₂SO₄, and concentrated in vacuo to afford the intermediate,2,3-dibenzoyloxy D-tartaric acid mono-hydroxamate. This compound wassuspended in toluene, heated under reflux for 2 h, then cooled to roomtemperature to form a 1 crystalline solid. The product was collected byfiltration, washed with a mixture of ether and hexane (1:1), and driedunder vacuum to afford the title compound (27) (58 g, 93% yield). ¹H NMR(CDCl₃, 400 MHz): δ 6.06 (s, 2H), 7.50 (t, 4H), 7.65 (dt, 2H), 8.06 (m,4H). MS (ESI) m/z 354.00 (M-H)⁻.

Step C:(1R)-1-[((3S,4S)-2,5-Dioxo-3,4-dibenzoyloxypyrrolidinyl)-oxycarbonyloxy]-2-methylpropyl2-methylpropanoate (25)

To a stirred solution of compound (27) (35 g, 98.6 mmol) andthiocarbonate (11) (34.6 g, 148 mmol) in dichloromethane at 0° C. wasdropwise added a 32% solution of peracetic acid (300 mmol) in aceticacid over 2 h. The reaction temperature was kept below 35° C. during theaddition of peracetic acid. After the addition was complete, thereaction mixture was stirred overnight at room temperature. Theresulting white precipitate was filtered and washed sequentially withwater and a mixture of ether and hexane (1:2), then dried under vacuumto afford the crude title compound. This product was crystallized oncefrom a mixture of ethyl acetate and hexane (1:1) to afford the titlecompound (25) (13.7 g, 25% yield). The diastereomeric purity of theproduct was determined to be 98.4% d.e. by HPLC using a chiral column.¹H NMR (CDCl₃, 400 MHz): δ 1.06 (d, 6H), 1.22 (d, 3H), 1.22 (d, 3H),2.20 (m, 1H), 2.64 (hept., 1H), 6.01 (br. s, 2H), 6.64 (d, 1H), 7.47 (m,4H), 7.63 (m, 2H), 8.07 (m, 4H).

Example 22 Synthesis of(1S)-1-[((3R,4R)-2,5-Dioxo-3,4-dibenzoyloxypyrrolidinyl)-oxycarbonyloxy]-2-methylpropyl2-methylpropanoate (28) Step A:(3R,4R)-2,5-Dioxo-3,4-dibenzoyloxy-3,4-dihydrofuran (29)

To a 3-necked 5 L round bottom flask fitted with a mechanical stirrerand a Teflon coated thermocouple was added (−)-2,3-dibenzoyl-L-tartaricacid (1000 g, 2.79 mol) followed by acetic anhydride (2 L). Thesuspension was stirred and heated to 85° C. for 2 h during which timethe starting material gradually dissolved. A short time thereafter, theproduct began to crystallize in the reaction mixture and the suspensionwas then cooled to 25° C. The product was collected by filtration,washed with 10% acetone in hexane (2×1 L), and dried in a vacuum oven at50° C. overnight to afford the title compound (29) as a white solid. ¹HNMR (CDCl₃, 400 MHz): δ 6.0 (s, 2H), 7.45 (app. t, 4H), 7.65 (app. t,2H), 8.05 (d, 4H).

Step B: 1-Hydroxy-(3R,4R)-2,5-Dioxo-3,4-dibenzoyloxypyrrolidine (30)

To a 3-neck 5 L round bottom flask fitted with a mechanical stirrer anda Teflon coated temperature probe was added compound (29) (2.79 mol)followed by acetonitrile (2 L). The suspension was cooled in an ice bathto 4° C., followed by the addition of 50% aqueous hydroxylamine (180 mL,2.93 tool) over 1 h. The starting material gradually dissolved duringthe addition and the reaction mixture was warmed to 20° C. and stirredfor 1 h. The reaction mixture was concentrated in vacuo, diluted withEtOAc (1 L) and washed with 1 N HCl (2×1 L). The organic phase wasseparated and concentrated in vacuo to afford a viscous red syrup. Thesyrup was then heated for two hours in toluene (2.5 L) at 100° C. withazeotropic removal of water. The syrup gradually dissolved and then theproduct crystallized. After cooling to room temperature the solid wascollected by filtration, washed with 10% acetone in hexane (2×1 L), anddried in a vacuum oven to afford the title compound (30) (862 g, 2.43mol, 87% yield) as a white solid. ¹H NMR (CDCl₃, 400 MHz): δ 5.85 (s,2H), 7.45 (app. t, 4H), 7.65 (app t, 2H), 8.05 (m, 4H).

Step C:(1S)-1-[((3R,4R)-2,5-Dioxo-3,4-dibenzoyloxypyrrolidinyl)-oxycarbonyloxy]-2-methylpropyl2-methylpropanoate (28)

A 3 L three necked round bottom flask fitted with a mechanical stirrer,Teflon coated temperature probe and an addition funnel was charged withcompound (11) (234 g, 1 mol), compound (30) (330 g, 0.95 mol), and1,2-dichloroethane (2200 mL). The reaction mixture was cooled under anitrogen atmosphere in an ice water bath to 15° C. To the stirredreaction mixture was added a 39% solution of peracetic acid in diluteacetic acid (500 mL, 2.94 mol) over 2 h, maintaining the temperaturebetween 15° C. and 22° C. This temperature was maintained for anadditional 12 h during which time a white precipitate was formed. Thereaction mixture was further cooled to 3-4° C., the product collected byfiltration, and washed with hexane (2×1 L). The product was dried invacuo, yielding the title compound (28) (128 g, 0.24 mol, 25% yield).The diastereomeric purity of the product was determined to be >99% d.e.by HPLC using a chiral column. ¹H NMR (CDCl₃, 400 MHz): δ 1.0 (d, 6H),1.2 (dd, 6H), 2.1 (m, 1H), 2.65 (m, 1H), 6.0 (br. s, 2H), 6.6 (d, 1H),7.45 (app. t, 4H), 7.65 (app. t, 2H), 8.05 (d, 4H).

Example 23 Synthesis of 3-{[1-Isobutanoyloxyethoxy]carbonylamino}propylSulfinic Acid (31)

To a solution of 3-aminopropylsulfinic acid (10 mmol) and sodiumbicarbonate (20 mmol) in water (40 mL) is added a solution of compound(17) (10 mmol) in acetonitrile (20 mL) over 1 min. The reaction isstirred at ambient temperature for 16 h. The reaction mixture is dilutedwith diethyl ether (100 mL) and washed with 0.1 M aqueous potassiumbisulfate (3×100 mL). The organic phase is separated, dried overanhydrous magnesium sulfate, filtered, and concentrated in vacuo toafford the title compound (31) as a white solid.

Example 24 Synthesis of 3-{[1-Butanoyloxyethoxy]carbonylamino}propylSulfinic Add (32)

Following the procedure of Example 23 and replacing compound (17) withcompound (18) affords the title compound (32) as a white solid.

Example 25 Synthesis of 3-{[1-Pivaloyloxyethoxy]carbonylamino}propylSulfinic Acid (33)

Following the procedure of Example 23 and replacing compound (17) withcompound (19) affords the title compound (33) as a white solid.

Example 26 Synthesis of3-{[1-Cyclohexanoyloxyethoxy]carbonylamino}propyl Sulfinic Acid (34)

Following the procedure of Example 23 and replacing compound (17) withcompound (20) affords the title compound (34) as a white solid.

Example 27 Synthesis of 3-{[Isobutanoyloxymethoxy]carbonylamino}propylSulfinic Acid (35)

Following the procedure of Example 23 and replacing compound (17) withcompound (21) affords the title compound (35) as a white solid.

Example 28 Synthesis of 3-{[1-Butanoyloxymethoxy]carbonylamino}propylSulfinic Acid (36)

Following the procedure of Example 23 and replacing compound (17) withcompound (22) affords the title compound (36) as a white solid.

Example 29 Synthesis of 3-{[Pivaloyloxymethoxy]carbonylamino}propylSulfinic Acid (37)

Following the procedure of Example 23 and replacing compound (17) withcompound (23) affords the title compound (37) as a white solid.

Example 30 Synthesis of 3-{[Cyclohexanoyloxymethoxy]carbonylamino}propylSulfinic Acid (38)

Following the procedure of Example 23 and replacing compound (17) withcompound (24) affords the title compound (38) as a white solid.

Example 31 Synthesis of3-{[(1R)-Isobutanoyloxyisobutoxy]carbonylamino}propyl Sulfinic Acid (39)

To a 3 L three necked round bottom flask fitted with a mechanicalstirrer, temperature probe, and nitrogen inlet is added compound (25)(100 mmol), 3-aminopropylsulfinic acid (100 mmol), THF (1 L), and water(100 mL). The suspension is stirred under a nitrogen atmosphere at18-20° C. for 4 h during which time the reaction mixture becomeshomogeneous. The THF is removed in vacuo and the reaction mixture isdiluted with methyl tert-butyl ether (250 mL) and washed with 1N HCl(1×500 mL) and water (2×200 mL). The organic phase is separated andconcentrated in vacuo to leave a white solid. The solid is purified byflash chromatography to afford the title compound (39) as a white solid.

Example 32 Synthesis of3-{[(1S)-Isobutanoyloxyisobutoxy]carbonylamino}propyl Sulfinic Acid (40)

Following the procedure of Example 31 and replacing compound (25) withcompound (28) affords the title compound (40) as a white solid.

Example 33 Synthesis of3-{[1-Isobutanoyloxyethoxy]carbonylamino}-(2R)-hydroxypropyl SulfinicAcid (41)

Following the procedure of Example 23 and replacing3-aminopropylsulfinic acid with 3-amino-(2R)-hydroxypropylsulfinic acidaffords the title compound (41) as a white solid.

Example 34 Synthesis of3-{[1-Butanoyloxyethoxy]carbonylamino}-(2R)-hydroxypropyl Sulfinic Acid(42)

Following the procedure of Example 24 and replacing3-aminopropylsulfinic acid with 3-amino-(2R)-hydroxypropylsulfinic acidaffords the title compound (42) as a white solid.

Example 35 Synthesis of3-{[1-Pivaloyloxyethoxy]carbonylamino}-(2R)-hydroxypropyl Sulfinic Acid(43)

Following the procedure of Example 25 and replacing3-aminopropylsulfinic acid with 3-amino-(2R)-hydroxypropylsulfinic acidaffords the title compound (43) as a white solid.

Example 36 Synthesis of3-{[1-Cyclohexanoyloxyethoxy]carbonylamino}-(2R)-hydroxypropyl SulfinicAcid (44)

Following the procedure of Example 26 and replacing3-aminopropylsulfinic acid with 3-amino-(2R)-hydroxypropylsulfinic acidaffords the title compound (44) as a white solid.

Example 37 Synthesis of3-{[Isobutanoyloxymethoxy]carbonylamino}-(2R)-hydroxypropyl SulfinicAcid (45)

Following the procedure of Example 27 and replacing3-aminopropylsulfinic acid with 3-amino-(2R)-hydroxypropylsulfinic acidaffords the title compound (45) as a white solid.

Example 38 Synthesis of3-{[Butanoyloxymethoxy]carbonylamino}-(2R)-hydroxypropyl Sulfinic Acid(46)

Following the procedure of Example 28 and replacing3-aminopropylsulfinic acid with 3-amino-(2R)-hydroxypropylsulfinic acidaffords the title compound (46) as a white solid.

Example 39 Synthesis of3-{[Pivaloyloxymethoxy]carbonylamino}-(2R)-hydroxypropyl Sulfinic Acid(47)

Following the procedure of Example 29 and replacing3-aminopropylsulfinic acid with 3-amino-(2R)-hydroxypropylsulfinic acidaffords the title compound (47) as a white solid.

Example 40 Synthesis of3-{[Cyclohexanoyloxymethoxy]carbonylamino}-(2R)-hydroxypropyl SulfinicAcid (48)

Following the procedure of Example 30 and replacing3-aminopropylsulfinic acid with 3-amino-(2R)-hydroxypropylsulfinic acidaffords the title compound (48) as a white solid.

Example 41 Synthesis of3-{[(1R)-Isobutanoyloxyisobutoxy]carbonylamino}-(2R)-hydroxypropylSulfinic Acid (49)

Following the procedure of Example 31 and replacing3-aminopropylsulfinic acid with 3-amino-(2R)-hydroxypropylsulfinic acidaffords the title compound (49) as a white solid.

Example 42 Synthesis of3-{[(1S)-Isobutanoyloxyisobutoxy]carbonylamino}-(2R)-hydroxypropylSulfinic Acid (50)

Following the procedure of Example 32 and replacing3-aminopropylsulfinic acid with 3-amino-(2R)-hydroxypropylsulfinic acidaffords the title compound (50) as a white solid.

Example 43 Synthesis of3-{[1-Isobutanoyloxyethoxy]carbonylamino}-(2S)-hydroxypropyl SulfinicAcid (51)

Following the procedure of Example 23 and replacing3-aminopropylsulfinic acid with 3-amino-(2S)-hydroxypropylsulfinic acidaffords the title compound (51) as a white solid.

Example 44 Synthesis of3-{[1-Butanoyloxyethoxy]carbonylamino}-(2S)-hydroxypropyl Sulfinic Acid(52)

Following the procedure of Example 24 and replacing3-aminopropylsulfinic acid with 3-amino-(2S)-hydroxypropylsulfinic acidaffords the title compound (52) as a white solid.

Example 45 Synthesis of3-{[1-Pivaloyloxyethoxy]carbonylamino}-(2S)-hydroxypropyl Sulfinic Add(53)

Following the procedure of Example 25 and replacing3-aminopropylsulfinic acid with 3-amino-(2S)-hydroxypropylsulfinic acidaffords the title compound (53) as a white solid.

Example 46 Synthesis of3-{[1-Cyclohexanoyloxyethoxy]carbonylamino}-(2S)-hydroxypropyl SulfinicAdd (54

Following the procedure of Example 26 and replacing3-aminopropylsulfinic acid with 3-amino-(2S)-hydroxypropylsulfinic acidaffords the title compound (54) as a white solid.

Example 47 Synthesis of3-{[Isobutanoyloxymethoxy]carbonylamino}-(2S)-hydroxypropyl SulfinicAcid (55)

Following the procedure of Example 27 and replacing3-aminopropylsulfinic acid with 3-amino-(2S)-hydroxypropylsulfinic acidaffords the title compound (55) as a white solid.

Example 48 Synthesis of3-{[Butanoyloxymethoxy]carbonylamino}-(2S)-hydroxypropyl Sulfinic Acid(56)

Following the procedure of Example 28 and replacing3-aminopropylsulfinic acid with 3-amino-(2S)-hydroxypropylsulfinic acidaffords the title compound (56) as a white solid.

Example 49 Synthesis of3-{[Pivaloyloxymethoxy]carbonylamino}-(2S)-hydroxypropyl Sulfinic Acid(57)

Following the procedure of Example 29 and replacing3-aminopropylsulfinic acid with 3-amino-(2S)-hydroxypropylsulfinic acidaffords the title compound (57) as a white solid.

Example 50 Synthesis of3-{[Cyclohexanoyloxymethoxy]carbonylamino}-(2S)-hydroxypropyl SulfinicAcid (58)

Following the procedure of Example 30 and replacing3-aminopropylsulfinic acid with 3-amino-(2S)hydroxypropylsulfinic acidaffords the title compound (58) as a white solid.

Example 51 Synthesis of3-{[(1R)-Isobutanoyloxyisobutoxy]carbonylamino}-(2S)-hydroxypropylSulfinic Acid (59)

Following the procedure of Example 31 and replacing3-aminopropylsulfinic acid with 3-amino-(2S)-hydroxypropylsulfinic acidaffords the title compound (59) as a white solid.

Example 52 Synthesis of3-{[(1S)-Isobutanoyloxyisobutoxy]carbonylamino}-(2S)-hydroxypropylSulfinic Acid (60)

Following the procedure of Example 32 and replacing3-aminopropylsulfinic acid with 3-amino-(2S)-hydroxypropylsulfinic acidaffords the title compound (60) as a white solid.

Example 53 Synthesis of3-{[1-Isobutanoyloxyethoxy]carbonylamino}-(2R)-fluoropropyl SulfinicAcid (61)

Following the procedure of Example 23 and replacing3-aminopropylsulfinic acid with 3-amino-(2R)-fluoropropylsulfinic acidaffords the title compound (61) as a white solid.

Example 54 Synthesis of3-{[1-Butanoyloxyethoxy]carbonylamino}-(2R)-fluoropropyl Sulfinic Acid(62)

Following the procedure of Example 24 and replacing3-aminopropylsulfinic acid with 3-amino-(2R)-fluoropropylsulfinic acidaffords the title compound (62) as a white solid.

Example 55 Synthesis of3-{[1-Pivaloyloxyethoxy]carbonylamino}-(2R)-fluoropropyl Sulfinic Acid(63)

Following the procedure of Example 25 and replacing3-aminopropylsulfinic acid with 3-amino-(2R)-fluoropropylsulfinic acidaffords the title compound (63) as a white solid.

Example 56 Synthesis of3-{[1-Cyclohexanoyloxyethoxy]carbonylamino}-(2R)-fluoropropyl SulfinicAcid (64)

Following the procedure of Example 26 and replacing3-aminopropylsulfinic acid with 3-amino-(2R)-fluoropropylsulfinic acidaffords the title compound (64) as a white solid.

Example 57 Synthesis of3-{[Isobutanoyloxymethoxy]carbonylamino}-(2R)-fluoropropyl Sulfinic Acid(65)

Following the procedure of Example 27 and replacing3-aminopropylsulfinic acid with 3-amino-(2R)-fluoropropylsulfinic acidaffords the title compound (65) as a white solid.

Example 58 Synthesis of3-{[Butanoyloxymethoxy]carbonylamino}-(2R)-fluoropropyl Sulfinic Acid(66)

Following the procedure of Example 28 and replacing3-aminopropylsulfinic acid with 3-amino-(2R)-fluoropropylsulfinic acidaffords the title compound (66) as a white solid.

Example 59 Synthesis of3-{[Pivaloyloxymethoxy]carbonylamino}-(2R)-fluoropropyl Sulfinic Acid(67)

Following the procedure of Example 29 and replacing3-aminopropylsulfinic acid with 3-amino-(2R)-fluoropropylsulfinic acidaffords the title compound (67) as a white solid.

Example 60 Synthesis of3-{[Cyclohexanoyloxymethoxy]carbonylamino}-(2R)-fluoropropyl SulfinicAdd (68)

Following the procedure of Example 30 and replacing3-aminopropylsulfinic acid with 3-amino-(2R)-fluoropropylsulfinic acidaffords the title compound (68) as a white solid.

Example 61 Synthesis of3-{[(1R)-Isobutanoyloxyisobutoxy]carbonylamino}-(2R)-fluoropropylSulfinic Acid (69)

Following the procedure of Example 31 and replacing3-aminopropylsulfinic acid with 3-amino-(2R)-fluoropropylsulfinic acidaffords the title compound (69) as a white solid.

Example 62 Synthesis of3-{[(1S)-Isobutanoyloxyisobutoxy]carbonylamino}-(2R)-fluoropropylSulfinic Acid (70)

Following the procedure of Example 32 and replacing3-aminopropylsulfinic acid with 3-amino-(2R)-fluoropropylsulfinic acidaffords the title compound (70) as a white solid.

Example 63 Synthesis of3-{[1-Isobutanoyloxyethoxy]carbonylamino}-(2S)-fluoropropyl SulfinicAcid (71)

Following the procedure of Example 23 and replacing3-aminopropylsulfinic acid with 3-amino-(2S)-fluoropropylsulfinic acidaffords the title compound (71) as a white solid.

Example 64 Synthesis of3-{[1-Butanoyloxyethoxy]carbonylamino}-(2S)-fluoropropyl Sulfinic Acid(72)

Following the procedure of Example 24 and replacing3-aminopropylsulfinic acid with 3-amino-(2S)-fluoropropylsulfinic acidaffords the title compound (72) as a white solid.

Example 65 Synthesis of3-{[1-Pivaloyloxyethoxy]carbonylamino}-(2S)-fluoropropyl Sulfinic Acid(73)

Following the procedure of Example 25 and replacing3-aminopropylsulfinic acid with 3-amino-(2S)-fluoropropylsulfinic acidaffords the title compound (73) as a white solid.

Example 66 Synthesis of3-{[1-Cyclohexanoyloxyethoxy]carbonylamino}-(2S)-fluoropropyl SulfinicAcid (74)

Following the procedure of Example 26 and replacing3-aminopropylsulfinic acid with 3-amino-(2S)-fluoropropylsulfinic acidaffords the title compound (74) as a white solid.

Example 67 Synthesis of3-{[Isobutanoyloxymethoxy]carbonylamino}-(2S)-fluoropropyl Sulfinic Acid(75)

Following the procedure of Example 27 and replacing3-aminopropylsulfinic acid with 3-amino-(2S)-fluoropropylsulfinic acidaffords the title compound (75) as a white solid.

Example 68 Synthesis of3-{[Butanoyloxymethoxy]carbonylamino}-(2S)-fluoropropyl Sulfinic Acid(76)

Following the procedure of Example 2.8 and replacing3-aminopropylsulfinic acid with 3-amino-(2S)-fluoropropylsulfinic acidaffords the title compound (76) as a white solid.

Example 69 Synthesis of3-{[Pivaloyloxymethoxy]carbonylamino}-(2S)-fluoropropyl Sulfinic Acid(77)

Following the procedure of Example 29 and replacing3-aminopropylsulfinic acid with 3-amino-(2S)-fluoropropylsulfinic acidaffords the title compound (77) as a white solid.

Example 70 Synthesis of3-{[Cyclohexanoyloxymethoxy]carbonylamino}-(2S)-fluoropropyl SulfinicAcid (78)

Following the procedure of Example 30 and replacing3-aminopropylsulfinic acid with 3-amino-(2S)-fluoropropylsulfinic acidaffords the title compound (78) as a white solid.

Example 71 Synthesis of3-{[(1R)-Isobutanoyloxyisobutoxy]carbonylamino}-(2S)-fluoropropylSulfinic Acid (79)

Following the procedure of Example 31 and replacing3-aminopropylsulfinic acid with 3-amino-(2S)-fluoropropylsulfinic acidaffords the title compound (79) as a white solid.

Example 72 Synthesis of3-{[(1S)-Isobutanoyloxyisobutoxy]carbonylamino}-(2S)-fluoropropylSulfinic Acid (80)

Following the procedure of Example 32 and replacing3-aminopropylsulfinic acid with 3-amino-(2S)-fluoropropylsulfinic acidaffords the title compound (80) as a white solid.

Example 73 Synthesis of3-{[1-Isobutanoyloxyethoxy]carbonylamino}-2-oxopropyl Sulfinic Acid (81)

Following the procedure of Example 23 and replacing3-aminopropylsulfinic acid with 3-amino-2-oxopropylsulfinic acid affordsthe title compound (81) as a white solid.

Example 74 Synthesis of3-{[1-Butanoyloxyethoxy]carbonylamino}-2-oxopropyl Sulfinic Acid (82)

Following the procedure of Example 24 and replacing3-aminopropylsulfinic acid with 3-amino-2-oxopropylsulfinic acid affordsthe title compound (82) as a white solid.

Example 75 Synthesis of3-{[1-Pivaloyloxyethoxy]carbonylamino}-2-oxopropyl Sulfinic Acid (83)

Following the procedure of Example 25 and replacing3-aminopropylsulfinic acid with 3-amino-2-oxopropylsulfinic acid affordsthe title compound (83) as a white solid.

Example 76 Synthesis of3-{[1-Cyclohexanoyloxyethoxy]carbonylamino}-2-oxopropyl Sulfinic Acid(84)

Following the procedure of Example 26 and replacing3-aminopropylsulfinic acid with 3-amino-2-oxopropylsulfinic acid affordsthe title compound (84) as a white solid.

Example 77 Synthesis of3-{[Isobutanoyloxymethoxy]carbonylamino}-2-oxopropyl Sulfinic Acid (85)

Following the procedure of Example 27 and replacing3-aminopropylsulfinic acid with 3-amino-2-oxopropylsulfinic acid affordsthe title, compound (85) as a white solid.

Example 78 Synthesis of3-{[Butanoyloxymethoxy]carbonylamino}-2-oxopropyl Sulfinic Acid (86)

Following the procedure of Example 28 and replacing3-aminopropylsulfinic acid with 3-amino-2-oxopropylsulfinic acid affordsthe title compound (86) as a white solid.

Example 79 Synthesis of3-{[Pivaloyloxymethoxy]carbonylamino}-2-oxopropyl Sulfinic Acid (87)

Following the procedure of Example 29 and replacing3-aminopropylsulfinic acid with 3-amino-2-oxopropylsulfinic acid affordsthe title compound (87) as a white solid.

Example 80 Synthesis of3-{[Cyclohexanoyloxymethoxy]carbonylamino}-2-oxopropyl Sulfinic Acid(88)

Following the procedure of Example 30 and replacing3-aminopropylsulfinic acid with 3-amino-2-oxopropylsulfinic acid affordsthe title compound (88) as a white solid.

Example 81 Synthesis of3-{[(1R)-Isobutanoyloxyisobutoxy]carbonylamino}-2-oxopropyl SulfinicAcid (89)

Following the procedure of Example 31 and replacing3-aminopropylsulfinic acid with 3-amino-2-oxopropylsulfinic acid affordsthe title compound (89) as a white solid.

Example 82 Synthesis of3-{[(1S)-Isobutanoyloxyisobutoxy]carbonylamino}-2-oxopropyl SulfinicAcid (90)

Following the procedure of Example 32 and replacing3-aminopropylsulfinic acid with 3-amino-2-oxopropylsulfinic acid affordsthe title compound (90) as a white solid.

Example 83 Standard Methods for Determination of Enzymatic Cleavage ofProdrugs in Vitro

For orally administered prodrugs, it is generally desirable that theprodrug remains intact (i.e., uncleaved) while in the gastrointestinaltract and be cleaved (i.e., to release the parent drug) while in thesystemic circulation. A useful level of stability can at least in partbe determined by the mechanism and kinetics of absorption of the prodrugby the gastrointestinal tract. A useful level of lability can at leastin part be determined by the pharmacokinetics of the prodrug and parentdrug in the systemic circulation. In general, prodrugs that are morestable in a Caco-2 S9 and/or pancreatin assay and are more labile in arat plasma, human plasma, rat liver S9, and/or human liver 89preparation can be useful as an orally administered prodrug. The resultsof tests, such as those described in this example, for determining theenzymatic cleavage of prodrugs in vitro can be used to select prodrugsfor in vivo testing.

The stabilities of prodrugs are evaluated in one or more in vitrosystems using a variety of preparations following methods known in theart. Tissues and preparations are obtained from commercial sources(e.g., Pel-Freez Biologicals, Rogers, A R, or GenTest Corporation,Woburn, Mass.). Experimental conditions useful for the in vitro studiesare described in Table 1. Each preparation is incubated with testcompound at 37° C. for one hour. Aliquots (50 μL) are removed at 0, 30,and 60 min and quenched with 0.1% trifluoroacetic acid in acetonitrile.Samples are then centrifuged and analyzed by LC/MS/MS. Stability ofprodrugs towards specific enzymes (e.g., peptidases, etc.) are alsoassessed in vitro by incubation with the purified enzyme:

Pancreatin Stability: Stability studies are conducted by incubatingprodrug (5 μM) with 1% (w/v) pancreatin (Sigma, P-1625, from porcinepancreas) in 0.025 M Tris buffer containing 0.5 M NaCl (pH 7.5) at 37°C. for 60 min. The reaction is stopped by addition of 2 volumes ofmethanol. After centrifugation at 14,000 rpm for 10 min, the supernatantis removed and analyzed by LC/MS/MS.

Caco-2 Homogenate S9 Stability: Caco-2 cells are grown for 21 days priorto harvesting. Culture medium are removed and cell monolayers are rinsedand scraped off into ice-cold 10 mM sodium phosphate 0.15 M potassiumchloride, pH 7.4. Cells are lysed by sonication at 4° C. using a probesonicator. Lysed cells are then transferred into 1.5 mL centrifuge vialsand centrifuged at 9000 g for 20 min at 4° C. The resulting supernatant(Caco-2 cell homogenate S9 fraction) is aliquoted into 0.5 mL vials andstored at −80° C. until used.

For stability studies, prodrug (5 μM) is incubated in Caco-2 homogenateS9 fraction (0.5 mg protein per mL) for 60 ruin at 37° C. Concentrationsof intact prodrug and released parent drug are determined at zero timeand 60 minutes using LC/MS/MS.

TABLE 1 Standard Conditions for Prodrug In Vitro Metabolism StudiesSubstrate Preparation Concentration Cofactors Rat Plasma 2.0 μM NoneHuman Plasma 2.0 μM None Rat Liver S9 2.0 μM NADPH* (0.5 mg/mL) HumanLiver S9 2.0 μM NADPH* (0.5 mg/mL) Human Intestine S9 2.0 μM NADPH* (0.5mg/mL) Caco-2 Homogenate 5.0 μM None Pancreatin 5.0 μM None *NADPHgenerating system, e.g., 1.3 mM NADP⁺, 3.3 mM glucose-6-phosphate, 0.4U/mL glucose-6-phosphate dehydrogenase, 3.3 mM magnesium chloride and0.95 mg/mL potassium phosphate, pH 7.4.

Example 84 Bioavailability of Prodrugs and Metabolites Thereof FollowingIntracolonic Administration in Rats Step A: Administration Protocol

Rats are obtained commercially and are pre-cannulated in the both theascending colon and the jugular vein. Animals are conscious at the timeof the experiment. All animals are fasted overnight and until 4 hourspost-dosing of a prodrug of 3-aminopropylsulfinic acid or analogthereof. A 3-aminopropylsulfinic acid or analog thereof or thecorresponding prodrug is administered as a solution (in water) directlyinto the colon via the cannula at a dose equivalent to about 75 mg orother appropriate dose of 3-aminopropylsulfinic acid or analog thereofper kg body weight. Blood samples (0.3 mL) are obtained from the jugularcannula at intervals over 8 hours and are quenched immediately byaddition of sodium metabisulfite to prevent oxidation of3-aminopropylsulfinic acid or analog thereof. Blood is then furtherquenched with methanol/perchloric acid to prevent hydrolysis of theprodrug. Blood samples are analyzed as described in Steps B and C.

Step B: Sample Preparation for Colonically Absorbed Drug

300 μL of methanol is added to 1.5 mL tubes. Rat blood (100 μL) iscollected at different times into the tubes and vortexed to mix. 90 μLof rat blood is quenched with 300 μL methanol. 10 μL of a standard stocksolution containing 3-aminopropylsulfinic acid or analog thereof (0.04,0.2, 1, 5, 25, and 100 μg/mL) and 20 μL of p-chlorophenylalanine isadded to 90 μL of rat blood to make up a final calibration standard(0.004, 0.02, 0.1, 0.5, 2.5, and 10 μg/mL). Samples are vortexed andcentrifuged at 3400 rpm for 20 min. The supernatant is analyzed byLC/MS/MS.

Step C: LC/MS/MS Analysis

An API 4000 LC/MS/MS spectrometer equipped with Agilent 1100 binarypumps and a CTC HTS-PAL autosampler are used in the analysis. AThermoHypersil-Keystone Betasil C18 100×4.6 mm, 5 μM column is usedduring the analysis. The mobile phase is 0.1% formic acid in water (A)and 0.1% formic acid in acetonitrile (B). The flow rate is 1.2 mL/min.The gradient condition is: 1% B for 0.5 min, then to 95% B for 1.8 min,and maintained at 95% B for 1.7 min. Then the mobile phase is returnedto 1% B for 2.5 min. A TurboIonSpray source is used on the API 4000. Theanalysis is done in negative ion mode for 3-aminopropylsulfinic acid andpositive ion mode for analogs of 3-aminopropylsulfinic acid and the MRMtransition for each analyte is optimized using standard solution. 20 μLof the samples are injected. Non-compartmental analysis is performedusing WinNonlin software (v.3.1 Professional Version, PharsightCorporation, Mountain View, Calif.) on individual animal profiles.Summary statistics on major parameter estimates is performed for C_(max)(peak observed concentration following dosing), T_(max) (time to maximumconcentration is the time at which the peak concentration was observed),AUC_((0-t)) (area under the plasma concentration-time curve from timezero to last collection time, estimated using the log-linear trapezoidalmethod), AUC_((0-∞)), (area under the plasma concentration time curvefrom time zero to infinity, estimated using the log-linear trapezoidalmethod to the last collection time with extrapolation to infinity), andt_(1/2,z) (terminal half-life).

Prodrugs that provide a bioavailability of the corresponding parent drugthat is greater than the bioavailability provided by an equimolar doseof the parent drug administered to a patient by the same route (e.g.,oral administration) can be useful as therapeutic agents.

Finally, it should be noted that there are alternative ways ofimplementing the embodiments disclosed herein. Accordingly, the presentembodiments are to be considered as illustrative and not restrictive,and the claims are not to be limited to the details given herein, butmay be modified within the scope and equivalents thereof.

1-23. (canceled)
 24. A method of treating spasticity or a symptom ofspasticity in a patient, comprising administering to a patient in needof such treatment a therapeutically effective amount of at least onecompound of Formula (I):

stereoisomers thereof, pharmaceutically acceptable salts of any of theforegoing, and pharmaceutically acceptable solvates of any of theforegoing, wherein: R¹ is selected from acyl, substituted acyl, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl; R² and R³ are independently selected from hydrogen,alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, and substituted heteroarylalkyl, or R² and R³ togetherwith the carbon atom to which they are bonded form a cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, or substitutedcycloheteroalkyl ring; R⁴ is selected from hydrogen, C₁₋₆ acyl,substituted C₁₋₆ acyl, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, aryl,substituted aryl, C₃₋₆ cycloalkyl, substituted C₃₋₆ cycloalkyl,heteroaryl, substituted heteroaryl, C₇₋₉ phenylalkyl, and substitutedC₇₋₉ phenylalkyl; R⁵ is selected from hydrogen, hydroxy, mercapto,fluoro, chloro, bromo, oxo, and 4-chlorophenyl; and R⁶ and R⁷ areindependently selected from hydrogen, C₁₋₆ alkyl, substituted C₁₋₆alkyl, C₁₋₆ alkoxy, substituted C₁₋₆ alkoxy, aryl, substituted aryl,C₃₋₆ cycloalkyl, substituted C₃₋₆ cycloalkyl, heteroaryl, substitutedheteroaryl, C₇₋₉ phenylalkyl, and substituted C₇₋₉ phenylalkyl.
 25. Amethod of treating gastroesophageal reflux disease in a patient,comprising administering to a patient in need of such treatment atherapeutically effective amount of at least one compound of Formula(I):

stereoisomers thereof, pharmaceutically acceptable salts of any of theforegoing, and pharmaceutically acceptable solvates of any of theforegoing, wherein: R¹ is selected from acyl, substituted acyl, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl; R² and R³ are independently selected from hydrogen,alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, and substituted heteroarylalkyl, or R² and R³ togetherwith the carbon atom to which they are bonded form a cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, or substitutedcycloheteroalkyl ring; R⁴ is selected from hydrogen, C₁₋₆ acyl,substituted C₁₋₆ acyl, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, aryl,substituted aryl, C₃₋₆ cycloalkyl, substituted C₃₋₆ cycloalkyl,heteroaryl, substituted heteroaryl, C₇₋₉ phenylalkyl, and substitutedC₇₋₉ phenylalkyl; R⁵ is selected from hydrogen, hydroxy, mercapto,fluoro, chloro, bromo, oxo, and 4-chlorophenyl; and R⁶ and R⁷ areindependently selected from hydrogen, C₁₋₆ alkyl, substituted C₁₋₆alkyl, C₁₋₆ alkoxy, substituted C₁₋₆ alkoxy, aryl, substituted aryl,C₃₋₆ cycloalkyl, substituted C₃₋₆ cycloalkyl, heteroaryl, substitutedheteroaryl, C₇₋₉ phenylalkyl, and substituted C₇₋₉ phenylalkyl.
 26. Amethod of treating drug addiction or abuse, alcohol addiction or abuse,or nicotine addiction or abuse in a patient, comprising administering toa patient in need of such treatment a therapeutically effective amountof at least one compound of Formula (I):

stereoisomers thereof, pharmaceutically acceptable salts of any of theforegoing, and pharmaceutically acceptable solvates of any of theforegoing, wherein: R¹ is selected from acyl, substituted acyl, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl; R² and R³ are independently selected from hydrogen,alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, and substituted heteroarylalkyl, or R² and R³ togetherwith the carbon atom to which they are bonded form a cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, or substitutedcycloheteroalkyl ring; R⁴ is selected from hydrogen, C₁₋₆ acyl,substituted C₁₋₆ acyl, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, aryl,substituted aryl, C₃₋₆ cycloalkyl, substituted C₃₋₆ cycloalkyl,heteroaryl, substituted heteroaryl, C₇₋₉ phenylalkyl, and substitutedC₇₋₉ phenylalkyl; R⁵ is selected from hydrogen, hydroxy, mercapto,fluoro, chloro, bromo, oxo, and 4-chlorophenyl; and R⁶ and R⁷ areindependently selected from hydrogen, C₁₋₆ alkyl, substituted C₁₋₆alkyl, C₁₋₆ alkoxy, substituted C₁₋₆ alkoxy, aryl, substituted aryl,C₃₋₆ cycloalkyl, substituted C₃₋₆ cycloalkyl, heteroaryl, substitutedheteroaryl, C₇₋₉ phenylalkyl, and substituted C₇₋₉ phenylalkyl.
 27. Amethod of treating cough or emesis in a patient, comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of at least one compound of Formula (I):

stereoisomers thereof, pharmaceutically acceptable salts of any of theforegoing, and pharmaceutically acceptable solvates of any of theforegoing, wherein: R¹ is selected from acyl, substituted acyl, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl; R² and R³ are independently selected from hydrogen,alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, and substituted heteroarylalkyl, or R² and R³ togetherwith the carbon atom to which they are bonded form a cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, or substitutedcycloheteroalkyl ring; R⁴ is selected from hydrogen, C₁₋₆ acyl,substituted C₁₋₆ acyl, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, aryl,substituted aryl, C₃₋₆ cycloalkyl, substituted C₃₋₆ cycloalkyl,heteroaryl, substituted heteroaryl, C₇₋₉ phenylalkyl, and substitutedC₇₋₉ phenylalkyl; R⁵ is selected from hydrogen, hydroxy, mercapto,fluoro, chloro, bromo, oxo, and 4-chlorophenyl; and R⁶ and R⁷ areindependently selected from hydrogen, C₁₋₆ alkyl, substituted C₁₋₆alkyl, C₁₋₆ alkoxy, substituted C₁₋₆ alkoxy, aryl, substituted aryl,C₃₋₆ cycloalkyl, substituted C₃₋₆ cycloalkyl, heteroaryl, substitutedheteroaryl, C₇₋₉ phenylalkyl, and substituted C₇₋₉ phenylalkyl.
 28. Themethod of any one of claims 24 to 27, wherein the compound of Formula(I) is administered as an oral dosage formulation.
 29. The method ofclaim 28, wherein the oral dosage formulation is a sustained releaseoral dosage formulation.
 30. The method of any one of claims 24 to 27,wherein the compound of Formula (I) is a prodrug of a3-aminopropylsulfinic acid analog selected from: 3-aminopropylsulfinicacid; (3-amino-2-(4-chlorophenyl)propyl)sulfinic acid;(3-amino-2-hydroxypropyl)sulfinic acid;(2S)-(3-amino-2-hydroxypropyl)sulfinic acid;(2R)-(3-amino-2-hydroxypropyl)sulfinic acid;(3-amino-2-fluoropropyl)sulfinic acid;(2S)-(3-amino-2-fluoropropyl)sulfinic acid;(2R)-(3-amino-2-fluoropropyl)sulfinic acid;(3-amino-2-oxopropyl)sulfinic acid; and pharmaceutically acceptablesalts thereof.
 31. The method of any one of claims 24 to 27, wherein R¹is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, phenyl, cyclohexyl, and 3-pyridyl; R² is selectedfrom hydrogen, methyl, n-propyl, and isopropyl; R³ is hydrogen; and R⁵is selected from hydrogen, hydroxy, fluoro, oxo, and 4-chlorophenyl; andeach of R⁴, R⁶, and R⁷ is hydrogen.